In addition to playing an important role in tumorigenesis, intestinal microbes also have a non-negligible value in the process of anti-cancer treatment.
There are many existing cancer therapies, such as chemotherapy and radiotherapy, which are effective, but have many side effects. Immunotherapy has its limitations, is ineffective and has limited targeting of cancer types. Studies have shown that the regulation of the gut microbiota not only helps to enhance the body's immunity and inhibit the proliferation and invasion of tumor cells, but also improves the tolerability of treatment and alleviates adverse reactions.
For example, studies have found that the toxicity of irinotecan in chemotherapy depends on the composition of the gut microbiota;
Trichoniaceae and Enterococciaceae reduce radiotherapy toxicity by producing short-chain fatty acids;
In patients with advanced melanoma, key bacteria such as Bifidobacteriaceae, Ruminococcae, and Trichuliniaceae have been associated with good outcomes after anti-PD1 therapy.
Therefore, it is worth digging and exploring how to better promote the recovery and efficacy of cancer patients by combining the gut microbiota with existing cancer treatment methods.
, microbiota and various cancer therapies, most notably immunotherapy and its immune-related adverse effects. Machine learning methods trained on the composition of a patient's microbiota can accurately predict a patient's ability to respond to immunotherapy.
Interventions such as fecal bacteria transplantation or diet, prebiotics, etc., can be used clinically to improve the success rate of immunotherapy in cancer patients, and new strategies for microbiota-based cancer therapy are discussed here.
Understanding the interrelationship between gut microbiota and cancer therapy can provide strong support for innovative therapeutic approaches and bring new breakthroughs in the field of oncology therapy.
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Microbiota and various types of cancer therapies
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Chemotherapy
Chemotherapy refers to the use of drugs to kill or control the growth of cancer cells. These drugs can be given to patients intravenously, orally, or topically.
shortcoming
Because the drugs used in chemotherapy may not be specific for cancer, they cannot distinguish between good and bad cells, which can affect other healthy tissues in the body and cause side effects such as hair loss, mouth ulcers, nausea, exhaustion, etc.
The gut microbiota influences chemotherapy pharmacokinetics, efficacy, and toxicity
A representative example is: the toxicity of irinotecan depends on the composition of the gut microbiota.
Note: Irinotecan is a topoisomerase I inhibitor for the treatment of colorectal cancer.
肝脏中:
葡萄糖醛酸转移酶将活性形式的伊立替康 SN-38 解毒成无活性的 SN-38-G。
In the intestines:
Many bacteria expressing β-glucuronidase convert SN-38-G back to SN-38, causing diarrhea.
This toxicity can be prevented with broad-spectrum antibiotics or β-glucuronidase inhibitors.
The intestinal flora can optimize tumor treatment and enhance immune and anti-cancer effects
The gut microbiota can modulate chemotherapy efficacy by providing a tumor microenvironment that favors the cytotoxic effects of drugs on cancer and maintaining anti-cancer adaptive immunity after drug-induced immunogenic cell death.
Oxaliplatin, cisplatin
In sterile or antibiotic-treated mice, the platinum-based compounds oxaliplatin and cisplatin showed reduced antitumor efficacy. These drugs can still form platinum-DNA adducts in tumors of mice depleted by microbiota, but no DNA damage has been observed. The gut microbiota initiates the production of reactive oxygen species (ROS) by myeloid cells in tumors via NOX2 (NADPH oxidase 2), which is required for platinum treatment-induced DNA damage.
Butyrate, a dietary fiber product fermented by gut microbes, can modulate the function of CD8+ T cells in the TME through IL-12 signaling, thereby enhancing the anticancer effects of oxaliplatin.
Alkylating agent cyclophosphamide (CTX)
Similarly, the efficacy of the alkylating agent cyclophosphamide also depends on the intestinal flora.
Note: The alkylating agent cyclophosphamide is both a chemotherapeutic agent and an immunosuppressant.
CTX reduces the phylum Firmicutes and spirochetes in the small intestine while increasing the abundance of other bacterial groups, some of which metastasize to mesenteric lymph nodes. CTX induces immunogenic tumor cell death, which relies on microbiota-regulated pathogenic helper T cells 17 (TH17) and memory TH1 cells.
CTX治疗后， Enterococcus hirae移位至淋巴结和Barnesiella intestinihominis在结肠中的积聚促进了癌症免疫。
In addition, the survival rate of cancer or ovarian cancer patients treated with chemotherapy immunotherapy was significantly correlated with that of E. Hirae and B. intestinihominis specific TH1 response.
Gemcitabine
Gemcitabine is a commonly used chemotherapy drug for pancreatic ductal adenocarcinoma. Gut microbiota is involved in the pharmacokinetics of chemotherapy drugs, and the efficacy of gemcitabine in the treatment of pancreatic ductal adenocarcinoma may be affected by gut microbiota.
γ-Proteobacteria are able to metabolize gemcitabine and convert it into inactive 2′,2′-difluorodeoxyuracil. Therefore, it is possible to improve the anti-cancer effect of gemcitabine in the future by combining antibiotics against γ-proteobacteria with chemotherapy.
In addition to negative effects, butyrate, an intestinal microbial metabolite, can enhance gemcitabine's efficacy against cancer cells by inducing apoptosis.
In addition to the gut microbiota, intratumoral bacteria promote tumor growth and interfere with chemotherapy efficacy, suggesting that:
The intratumoral microbiota may be the target of cancer therapy
Intratumoral microbiota has been shown in human breast, bone, pancreatic, ovarian, lung, melanoma, glioblastoma, and primary and metastatic colorectal cancers. The tumor microbiota may play an important role in tumorigenesis, tumor progression, and treatment response.
Tumor-associated γ-Proteobacteria express bacterial cytidine deaminase, which inactivates the cytotoxic drug gemcitabine; The use of the antibiotic ciprofloxacin clears the bacteria and restores sensitivity to gemcitabine. However, gemcitabine treatment also alters the gut microbiota by increasing the abundance of Proteus.
↓↓↓
Therefore, there is no definitive evidence as to whether antibiotic treatment affects tumor growth through specific effects on tumor-associated γ-proteobacteria or other microbial components associated with the gut or tumor.
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Mouse breast cancer model:
The intratumoral bacteria carried by circulating tumor cells reorganize the cytoskeleton and promote the survival of host cells. Direct injection of strains isolated from the tumor microbial community enhances metastasis formation.
Detected in primary human colon cancer and distant metastases:
——梭杆菌门（Fusobacteria）
Treatment with metronidazole antibiotics can eliminate Fusobacterium and reduce the rate of tumor growth.
Patients with liver cancer and cirrhosis:
The increased abundance of Stenotrophomonas maltophilia in the liver induces a cellular senescence-associated secretory phenotype (SASP) of hepatic stellate cells, thereby promoting hepatocarcinomagenesis.
↓↓↓
These data suggest that antibiotics have the potential to target the tumor microbiota, but that the systemic effects of antibiotic therapy may be antagonistic to the local effects of tumors, especially given the deleterious effects of antibiotics on immune checkpoint blockade.
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Intracellular bacteria may evade RAB11-mediated phagocytosis and inhabit stable bacterial-containing vacuoles, making them ineffective against antibiotics.
↓↓↓
Therefore, the use of cell-penetrating peptides and nucleic acids may maximize the potency of antibiotics against tumor-associated bacteria.
The gut microbiota regulates cancer therapy, which can improve the treatment effect and prevent adverse reactions in a targeted manner
doi: 10.1038/s41568-022-00513-x
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Radiation therapy
Radiation therapy is about shrinking or destroying tumors, but the process is different.
Radiation is a high-energy invisible light wave that targets cancer cells to destroy their genetic material, eventually killing them. The radiation waves damage cancer cells, which die over time and are removed by the body, causing the tumor to shrink.
Unlike chemotherapy, radiation therapy is usually a local treatment, meaning it doesn't spread throughout the body.
shortcoming
If nearby healthy tissue is damaged during treatment, local radiation may have side effects such as nausea, mouth sores, difficulty eating due to throat problems, dry skin, exhaustion, etc.
Different cancer types differ in toxicity and sensitivity, which is a major obstacle to the safety and effectiveness of ionizing radiation therapy.
Both bacterial and fungal components of the gut microbiota can contribute to heterogeneity among patients
In experimental animals, vancomycin, an antibiotic selective for gram-positive bacteria, improves the effectiveness of RTX by depleting short-chain fatty acid-producing gut bacteria, and enhances dendritic cell antigen presentation and cancer immunity.
Administration of butyrate to vancomycin-treated mice abolishes this effect in part by inhibiting dendritic cell function, including their ability to produce IL-12.
Treatment of the gut microbiota with broad-spectrum antibiotics leads to intestinal dilation of yeast-like fungi, inhibiting tumor immunity through signaling by the β-glucan receptor Dectin 1, thereby reducing RTX effectiveness. Treatment with antifungal agents improved RTX effectiveness in untreated mice, especially in mice that had a poor response to RTX after antibiotic treatment.
In breast cancer patients, the expression of Dectin1 in intratumoral myeloid cells was inversely correlated with survival, an observation suggesting that fungal immunosuppressive effects may be clinically relevant.
The Complex Functions of Short-Chain Fatty Acids in Cancer Therapy: Antitoxicity and Immunomodulation
Conventionally housed mice are more susceptible to total body irradiation (TBI) toxicity than germ-free mice, as the microbiota inhibits the expression of ANGPTL4.
NOTE: ANGPTL4, angiopoietin-like 4, also known as FIAF, is a lipoprotein lipase inhibitor that supports tissue repair.
However, short-chain fatty acid-producing bacteria protect RTX-treated patients from colitis and mucositis by inducing ANGPTL4.
Trichospiraceae and Enterococciaceae → produce propionic acid → reduce toxicity
Bacteria that produce tryptophan metabolites and short-chain fatty acids (particularly propionate), Lachnospiraceae and Enterococcaceae, are abundant in mice that survive total body irradiation, and resistance to TBI toxicity can be transferred to other mice.
The presence of Lachnospiraceae and Enterococcaceae was observed in stool samples of patients with leukemia during pretreatment for allogeneic hematopoietic stem cell transplantation (allo-HSCT). These patients experienced less severe enterotoxicity when treated with systemic radiotherapy (TBI).
These findings could explain why probiotics that produce short-chain fatty acids, such as lactobacilli and bifidobacteria, can prevent TBI toxicity.
Overall, several studies have shown that different short-chain fatty acids may have complex effects on cancer immunity and therapeutic toxicity, including mucosal protective effects, mediated in part by induction of ANGPTL4, IL-18, and IL-22, and opposing immunomodulatory effects mediated by Treg cell induction and inhibition of dendritic cell function.
Therefore, the function of short-chain fatty acids in radiotherapy and other cancer treatments appears to be complex and requires further research.
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immunotherapy
The latest cancer therapies use the host immune system to fight cancer. Immune cells inhibit the development of tumors by recognizing and destroying cancer cells.
CTLA-4 acts as an "off" switch for T cell activation in lymph nodes, while PD-L1/PD-1 reduces late immune responses at tumor sites.
Immune checkpoint inhibitors (ICIs) are monoclonal blocking antibodies that release the immune system's "brakes" so that immune cells can recognize and attack cancer cells more efficiently.
This approach has resulted in significant durable remissions for some patients with refractory cancers, such as advanced and metastatic melanoma, renal cell carcinoma, non-small cell lung cancer, and others. Currently used for more than 25 different tumor types.
shortcoming
Immunotherapy (ICI) costs more than $100,000 per patient per year, with a success rate of only 20%-40%, and many patients experience immune-related adverse events.
Thus, the rapidly evolving need highlights the need to extend the effectiveness of immunotherapy to all cancer patients.
The microbiota maintains resistance to pathogens and disease tolerance, preventing excessive inflammatory responses to harmless antigens.
Changes in diet, lifestyle, and the use of antibiotics and other medications may alter this ecological balance of health protection. Unlike antigen-specific resistance to acute infection, tumors suppress cancer immunity by hijacking disease tolerance mechanisms. Therefore, alterations in the gut microbiota may affect the patient's response to immunotherapy and the extent of immune-related adverse events (irAEs).
Adoptive T cell therapy (ACT): vancomycin enhances ACT anti-tumor, and other antibiotics decrease anti-tumor
Treatment with vancomycin increases the abundance of Proteus phylum in the gut but depletes most species of Firmicutes and Bacteroidetes, enhancing the antitumor effect of ACT in mice.
Other antibiotics, particularly neomycin and metronidazole, deplete gram-negative aerobic and anaerobic bacteria, respectively, reducing the antitumor effects of ACT.
Vancomycin-modified microbiota induces the production of IL-12 that stimulates T cells, maintaining adoptively metastatic cytotoxic T cells.
Toll样受体激动剂：CpG-ODN、ICB疗法
Gram-negative bacteria are associated with favorable innate responses to necrotic CpG-ODN, as well as redirection of the tumor microenvironment that maintains adaptive CD8+ T cell-mediated anticancer immunity.
Enhanced adaptive immunity with ICB therapy (as discussed later) is associated with the presence of several gram-positive bacteria, including:
- Ruminococcaceae
- Lachnospiraceae
- Bifidobacteriaceae
In this case, gram-negative bacteria are associated with an immunosuppressive state of local and systemic inflammation.
In a clinical trial (NCT03618641), the efficacy of the combination of CpG-ODN and ICB was demonstrated, and the initial CpG-ODN-induced necrosis and maintenance of recurrence-free survival under anti-PD1 therapy correlated with stool abundance in gram-negative bacteria (Proteobacteria, Bacteroidetes, and Gram-negative Oscillospiraceae).
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Immune checkpoint blockade
In general, only 20-40% of patients respond to ICB, so there is a need to identify response markers and develop treatments to overcome drug resistance.
The gut microbiota has emerged as an external tumor biomarker for predicting ICB response.
CTLA4
➦ Germ-free mice do not respond well to anti-CTLA4 treatment.
➥ 向微生物群耗尽的小鼠注射多形拟杆菌(Bacteroides thetaiotaomicron)或脆弱拟杆菌(Bacteroides fragilis)，通过诱导肿瘤中的DC成熟和引流淋巴结中的TH1反应，恢复抗CTLA4反应。
PDL1
Conversely, the resistance of mice to tumor growth and their responsiveness to PDL1 were related to fecal abundance of several bifidobacteria.
In patients with advanced melanoma, fecal abundance of key bacterial species of Actinomycea (Bifidobacterium and Coriobacteriaceae) and Firmicutes (Rumen Coccus and Triocillomyceae) was associated with good outcomes after anti-PD1 therapy.
In patients with lung, renal cell, or hepatocellular carcinoma, mucin-degraded Akkermansia muciniphila exerts antitumor effects in anti-PD1 therapy. However, in some patients treated with antibiotics, A. The high abundance of muciniphila is associated with resistance to anti-PD1 therapy, which may indicate that AKK bacteria have a bimodal effect in the response to anti-PD1 therapy.
Staphylococcus haemolyticus and Corynebacterium aurimucosum were higher in the stool of patients who did not respond to anti-PD1 therapy, and in patients with renal and lung cancer who responded, the stool frequency of E. hirae was higher.
The consistency of bacterial species found in the study is limited, possibly due to changes in ICB-mediated immune mechanisms.
TIM3
Antibiotic treatment against the damage of TIM3 cancer therapy has also been shown to play a role in the gut microbiota in maintaining the efficacy of this type of ICB.
The composition of gut, blood-associated microbiota, and tumor-associated microbiota differs and is specific for different types of cancer, resulting in different bacterial species having an impact on the response to immunotherapy.
Studies of cohorts of patients with the same type of tumour and the same ICB treatment reported more consistent results, even though they were still affected by the heterogeneity of the microbiota within the cohort.
In fact, unknown variations in complex microbial communities hinder robust feature recognition. Future studies that rely on new signatures of bacterial subspecies and strains, and analyze the associations of individual bacterial genes or pathways, will better identify the associations of specific bacteria with treatment response and their mechanisms of action.
Regulation of the gut microbiota in response to anti-PD1 immune checkpoint blockade
doi: 10.1038/s41568-022-00513-x
In studies and meta-analyses of most cancer patients receiving anti-PD1 therapy, bacteria that are universally associated with favorable or adverse treatment response have been consistently defined.
A healthy, non-inflammatory intestinal mucosa characterized by transcripts encoding anti-inflammatory apolipoproteins and transmembrane mucins was observed in patients who responded to anti-PD1 therapy. In the blood of these patients, cytokines and chemokines involved in T cell and B cell recruitment are elevated, which is important for anti-tumor immunity. The upper left corner lists the identified bacterial species associated with a favorable response to anti-PD1 therapy and their mechanisms of action in regulating anti-tumor immunity.
In patients who did not respond to anti-PD1 therapy, inflammation of the intestinal mucosa and detachment of inflammatory cells were observed, while in their blood there were often biomarkers of systemic inflammation. The listed intestinal gram-negative microbiota is associated with adverse effects of anti-PD1 therapy and biomarkers of local and systemic inflammation and may reflect the immunosuppressive tumor microenvironment.
Early clinical response depends on tumor intrinsic or host factors; The modulation of the gut microbiota was more influential about 1 year after the start of treatment
An anti-PD1 therapy study in melanoma patients reported an association between higher gut microbiota α diversity and a favorable response. But no more research confirms that α diversity is used to distinguish healthy individuals from cancer patients, and it does not predict responsiveness to immunotherapy.
A meta-analysis of published data on cohorts of melanoma patients receiving anti-PD1 therapy revealed commonalities between the identified bacteria, not only at the individual species level, but also within the larger taxonomic clade.
Most studies consider favorable microbiota signatures, including multiple members of Actinomycetes, as well as in Firmicutes, Rumen Coccaceae and Lachnospiraceae.
And an unfavorable feature includes Bacteroidetes and Proteobacteria.
Two meta-analyses of immunotherapy response in melanoma patients using large cohorts found that the baseline composition of the gut microbiota had a limited ability to distinguish between responding and non-responding patients when radiologically assessed at 3 months, but it could better distinguish between patients with and without progression at about 1 year after treatment initiation. In addition, patients with long-term progression-free survival maintained a good microbiota for several years after initiation of anti-PD1 therapy.
Why are certain bacteria not consistently identified as biomarkers in the cohort?
One study had samples from three European countries and some publicly available datasets, and included melanoma patients treated with anti-CTLA4, anti-PD1, or a combination of both. This relates to the heterogeneity of geography and type of treatment.
Even in identical twins, the gut microbiome of each individual is unique, and a large part of this uniqueness is encoded at the individual strain level. Analytical methods are needed to explore this individual-specific microbial diversity in greater depth.
Gut microbiome types differ in different geographic regions because the human gut microbiome is influenced by ethnic and geographic origin. Using more than 7,000 samples from the U.S. Gut Project, microbial types were geomapped, revealing uneven distribution across geographic regions of the United States.
The microbial types in the cohort of melanoma patients receiving anti-PD1 therapy are also not representative and reflect their geographic context. In addition, the probability of responding to anti-PD1 therapy correlates with gut microbiota type.
Therefore, analyzing the relationship between gut microbiota and immunotherapy response through a microbial type perspective provides a possible explanation for the inconsistencies of previous studies and can be used as a tool to correct geographical and clinical center-specific biases.
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Gut microbiota regulation mechanisms for cancer immunotherapy
Peptidoglycanase-mediated anticancer in the gut microbiota
The ability of some enterococci to maintain ICB action in mice is mediated by a cluster of peptidoglycan hydrolases, including the secretion of antigen a (SagA), which produces NOD2-activated muropeptides that enhance anti-PDL1-induced tumor immunity.
When administered to mice, SagA-transfected Lactococcus lactis inhibits tumor growth and improves anti-PD1 reactivity. Certain strains of Bifidobacterium bifidum that act synergistically with mouse anti-PD1 and oxaliplatin cancer therapy enrich peptidoglycan synthesis genes to stimulate cancer immunity via TLR2.
The intestinal microbiota regulates interferon
The intestinal microbiota maintains the expression of type I interferon and enhances tumor immunity
In microbiota-depleted mice, interferon signaling in innate immune cells within tumors is attenuated, altering macrophage polarization, dendritic cell differentiation, and DC-natural killer (NK) cell crosstalk, and shifting the tumor microenvironment from anti-tumor to pro-tumorial.
Gut microbes enhance the immune response through a series of receptors and signaling pathways by inducing immune cells to produce interferon.
注：一些列受体如TLR3、TLR4、TLR7、TLR9、Dectin 1、干扰素基因刺激因子（STING）、DDX41、RIG-I等。
Microbiota-induced cell and gene expression signatures activate the STING-interferon pathway in mice and are associated with a favorable ICB response in melanoma patients.
Certain commensal bacteria, such as AKK, Bifidobacteria, and Lactobacillus rhamnosus, inhibit tumor progression by activating the interferon pathway and enhance the effect of immunotherapy.
The effects of interferon are also related to the type of tumor and the stage of treatment
Type I interferon signaling is not always associated with inhibition of tumor growth. Persistent type I interferon signaling in the liver, either by inducing nitric oxide or altering the urea cycle, induces resistance to anti-PD1 therapy or inhibits antiviral T cell responses, respectively.
The production of interferon by different stimuli also has different effects on tumor growth and immune response. In tumor treatment, a detailed understanding of the effects of interferon on different cells at different time points and how it affects the tumor environment and the effect of immunotherapy needs to be further studied.
Intestinal pro-inflammatory: predicts poor response to ICB
Many peripheral blood biomarkers of systemic inflammation, such as high neutrophil-to-lymphocyte ratio (NLR) and elevated levels of C-reactive protein (CRP), IL-8, and serum amyloid a (SAA), are predictors of poor response to ICB.
In the fecal microbiota of melanoma patients, high NLR is associated with increased abundance of gram-negative bacteroidetes. Human fecal transcriptome analysis revealed the presence of pro-inflammatory features in the gut of patients who did not respond to anti-PD1 therapy, mainly caused by exfoliated neutrophils and other myeloid cells, which are associated with LPS and NF-κB signaling, leading to the production of pro-inflammatory cytokines such as TNF, IL-1, and IL-8.
Gram-negative bacteria: hinder the ICB response
Overall, these data suggest that gram-negative bacteria in the gut microbiota may induce immunosuppressive local intestinal and systemic inflammation through LPS production and TLR4 signaling, thereby hindering the ICB response.
Experimentally-induced cholestasis in mice induces the transfer of gram-negative bacteria from the intestine to the liver, resulting in a TLR4-dependent inflammatory response, the production of CXCL1, the recruitment of immunosuppressive neutrophils, and the inhibition of anti-tumor immunity, resulting in enhanced growth of cholangiocarcinoma. In addition, the association of the gram-negative bacterium Fusobacterium nucleanum with primary and metastatic colorectal cancer cancers is immunosuppressive by attracting myeloid cells.
Cross-reactivity between autoantigens and microbial xenoantigens
Cross-reactivity between autoantigens and microbial xenoantigens is common in autoimmune diseases and may be related to cancer immunity. The body develops an immune response not only to pathogens, but also to commensal microorganisms. Although this response is well controlled, dysregulation may trigger immunopathology and may be reactivated in patients treated with ICB, leading to immune-related adverse effects and possible cross-reactivity with tumor neoantigens.
Some tumor neoantigens identified in ICB-treated patients may have cross-reactivity with microbial antigens
In anti-CTLA4-treated mice, inhibition of MCA-205 sarcoma tumor growth is supported by adoptive transfer of B. thetaiotaomin-specific or B. fragilis-specific T cells resulting in their activation, supporting the idea of molecular mimetics between tumor and microbial antigens.
The mouse bacterial symbiosis E. hirae is associated with favorable responses to cyclophosphamide, which carries peptide-expressing prophages, against which it initiates major histocompatibility complex (MHC) class I reactions, and cross-reacts with epitopes in overexpressed non-mutant proteasomal components in cancer cells.
In humans, the same prophages are expressed in the genus Enterococci. With the exception of Trichomonas, its MHC-restricted epitope cross-reacts with an epitope in glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), which is also overexpressed in tumors.
In human melanoma metastases, bacterial species expressing human leukocyte antigen (HLA) class I and II restricted peptides are present in hematopoietic cells and tumor cells. Some of these peptides are able to specifically activate tumor-infiltrating lymphocytes when pulsed at EBV-transformed B cells expressing tumor-matched HLA alleles.
Therefore, it can be speculated that in patients, these peptides elicit a T-cell immune response that may affect anti-cancer immunity through the presentation of traditional antigen-presenting cells or melanoma cells.
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Microbiota metabolites
It is expected to be a biomarker for predicting response to immunotherapy
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Short-chain fatty acids
Short-chain fatty acids and radiotherapy were mentioned in the second section above, and here we will focus on the predictive role of short-chain fatty acids in cancer patients undergoing ICI.
In a study conducted in Japan, fecal short-chain fatty acids were associated with favorable clinical outcomes in 52 patients with solid tumors treated with anti-PD-1 antibodies. High concentrations of fecal acetate, propionate, butyrate, and valerate, as well as serum isovalerate, are associated with prolongation of PFS.
In contrast, other studies have found that high serum butyrate and propionate levels are associated with resistance to anti-CTLA4 antibodies and an increase in the number of Treg cells in melanoma patients.
Given that preclinical tumor models have also revealed the negative effects of short-chain fatty acids on their efficacy against CTLA4 antibodies or radiation therapy, further studies are needed to validate the predictive value of short-chain fatty acids in large geographically diverse cohorts before any short-chain fatty acids in blood or feces can be utilized as a biomarker of ICI efficacy.
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Inosine
Different bacterial species, including Bifidobacterium pseudolongum, Lactobacillus joseri, and Myxococcus, produce inosine and its metabolite hypoxanthine. These molecules bind to the adenosine receptor A2a (A2aR), activate anti-tumor T cells and improve ICB efficiency in mice, particularly anti-CTLA4 therapies.
Inosine enhances the therapeutic effect of anti-PD1
In addition to A2aR-mediated T cell activation, inosine is an alternative carbon source for CD8+ T cells under glucose restriction and enhances anti-PD1 therapeutic efficacy against tumors that cannot utilize inosine as an energy source. It has been shown that inosine activity enhances ICB efficacy and, like adenosine, activates A2aR, which is an immunosuppressive checkpoint that enhances ICB effect in trials of clinical cancer therapy.
Inosine may also suppress autoimmunity
Lactobacillus reuteri can prevent ICB-induced colitis but does not affect the antitumor efficacy of ICB in mice, and it inhibits autoimmunity in Treg cell-deficient Scurfy mice by enhancing inosine production acting on A2aR110.
These highly contradictory results may be explained by the fact that inosinate's direct stimulating effect on T cells is contextual; In germ-free animals or in vitro without pro-inflammatory priming provided by commensal bacteria, inosine requires inflammatory stimulation provided by CpG-ODN or IFNγ, respectively, under these experimental conditions. Due to the lack of this inflammatory stimulus, inosine does inhibit T cells.
Therefore, targeting inosinate-dependent pathways in cancer immunotherapy requires a better understanding of these contrasting effects of inosine, taking into account that the signals of adenosine and inosine via A2aR may not be the same, and that inosine affects different models of systemic inflammation via A2aR or A3R.
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tryptophan
Two studies investigated the clinical significance of the ratio of kynurenine to tryptophan (Kyn vs. Trp) in patients with advanced cancer undergoing ICIs.
A high Kyn/Trp ratio is associated with reduced overall survival
In the first study, the Kyn/Trp ratio was significantly higher in patients with early disease progression (within 3 months) than in responders (P = 0.017).
In the second study, an increase in the Kyn-to-Trp ratio (>50%) 4-6 weeks after initiation of treatment in melanoma and renal cell carcinoma patients treated with nivolumab was strongly associated with a reduction in median overall survival (P ≤ 0.026).
Controversial findings
Given the importance of metabolic adaptation in cancer immunotherapy and the poor efficacy of selective IDO1 inhibitors in combination with ICIs in melanoma patients (in the ECHO-301/KEYNOTE-252 Phase III trial), these findings call into question not only the need for patient stratification based on serum epinephrine/tryptophan ratio monitoring in future trials, but also the analysis of the dynamic regulation of gut microbiota during ICI therapy.
In fact, tryptophan is metabolized not only by tumors and myeloid cells, but also by different species in the gut microbiota into indole and indole derivatives, including indoleacetic acid, indole-3-aldehyde (I3A), and indole propionic acid, which are able to bind to aromatic hydrocarbon receptors.
May support a tryptophan-rich diet, or a combination of I3A or 3-IAA-based prebiotics with ICIs
When Lactobacillus reuteri is administered orally to mice in combination with ICI, it can translocate from the ileum to the melanoma site, release I3A, activate the TCR signaling pathway of CD8-positive T cells, and promote the release of IFNγ and anti-tumor effects.
The clinical significance of these experimental findings has been demonstrated in a study involving melanoma patients treated with ICIs, opening the way for the use of tryptophan-based dietary interventions in cancer patients.
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L-arginine
Intracellular L-arginine concentrations also directly affect the metabolic fitness and survival of T cells, thereby affecting their ability to mediate effective anti-tumor immune responses in mouse models.
Elevated L-arginine levels induced global metabolic changes, including the shift from glycolysis to oxidative phosphorylation in activated T cells, and promoted the production of central memory-like T cells.
Low serum L-arginine levels (<42 μM) were significantly and independently associated with reduced clinical benefit rates, progression-free survival, and overall survival in the discovery and validation groups (P = 0.004). In addition, low serum L-arginine levels were associated with increased expression of PD-L1 in myeloid cells. Therefore, plasma L-arginine monitoring may be a suitable predictive biomarker for ICI efficacy.
doi: 10.1038/s41571-023-00785-8.
04
Cancer therapies that target the gut microbiota
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antibiotic
Although broad-spectrum antibiotics may cause fungal overgrowth, which can reduce the efficiency of radiotherapy
Vancomycin depletes short-chain fatty acid bacteria and improves the effect of radiotherapy
An ongoing clinical trial (NCT03546829) testing whether vancomycin increases anti-tumor immunity as assessed by IFNγ production in patients with non-small cell cancer (NSCLC) undergoing stereotactic body radiation therapy.
Vancomycin also attenuates the growth of primary and metastatic cancers in mice by enhancing the migration of natural killer T cells (NKTs) in the liver and the production of IFNγ.
Vancomycin depletes gram-positive bacteria and regulates bile acids
Vancomycin depletes gram-positive bacteria, particularly Clostridium scindens, which converts primary bile acids to secondary bile acids. Microbiota-derived bile acids affect many aspects of inflammation, immunity, and carcinogens. Primary bile acids, such as chenodeoxycholic acid, induce the production of chemokine CXCL16 through sinusoidal endothelial cells, which attract NKT cells via CXCR6, while secondary bile acids, particularly omega-rat cholic acid, inhibit CXCL16 production.
Clinical trials (NCT03785210) are also planned to test whether vancomycin improves response to anti-PD1 therapy in patients with primary liver cancer or metastases. However, even specific antibiotics can cause widespread changes in the composition of the gut microbiota, which may have the opposite effect on cancer treatment.
The regulation of the immune response by bile acids is also complex
After FMT in melanoma patients, secondary bile acid levels are associated with a good clinical response to anti-PD1 therapy.
However, in mice, Bacteroidetes partially inhibits the secondary bile acid 3-oxoLCA in TH17 cells and converts it into isoalloLCA that activates Treg cells, thereby limiting autoimmunity and cancer immunity.
Vancomycin improves ADT efficacy
Castration-resistant prostate cancer is associated with changes in the gut microbiota that promote cancer, using an antibiotic cocktail containing vancomycin to deplete androgen-producing bacteria in mice, an antibiotic that can specifically reduce bacteria in the phylum Firmicutes, including androgen-producing Clostridium spp., thereby improving the effect of ADT (androgen deprivation therapy). Therefore, if antibiotics are used with ADT, their nature should be to selectively deplete androgen-producing bacteria rather than immunostimulatory species.
Antibiotic therapy remains challenging, and more specific approaches need to be explored
In general, the use of antibiotics during or before the ICB adversely affects the clinical response, most likely because they alter the intestinal ecology and the balance between favorable and unfavorable bacteria. While there may be benefits to targeting the gut microbiota with antibiotics (as in the example above), overall, this presents the challenge of the broad response of most antibiotics and the potential induction of antibiotic resistance.
In addition to antibiotics, more specific approaches, such as phage therapy and more effective and specific phage-mediated CRISPR-Cas3 antimicrobials, can be used more precisely after our understanding of the types of bacteria that directly affect the anti-tumor response and the ecological changes caused by their elimination.
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Michy transplantation
FMT can solve 80-90% of antibiotic-resistant Clostridium difficile infections, and others including various opportunistic infections and inflammatory bowel disease are also being studied.
For colitis after immunotherapy, FMT is effective
A common immune-related adverse reaction to anti-CTLA4 therapy is colitis, which can be severe and refractory to corticosteroid or TNF antagonists.
Two cancer patients developed colitis after ICB treatment and recovered quickly after FMT treatment with a healthy donor. Colonization of the donor flora did occur, with a decrease in the abundance of Firmicutes and Proteobacteria, and an increase in the abundance of Bacteroidetes and Verrumicrobiae. A subsequent preliminary report showed that 11 of the 15 cancer patients treated with FMT recovered from ICB-induced colitis.
FMT: Improving the efficacy of anti-PD1 therapy in melanoma patients
Two clinical trials have demonstrated that FMT can target the microbiota to improve anti-PD1 therapy efficacy in melanoma patients. As predicting microbiota composition is not yet feasible, this may support an anti-PD1 treatment response to select a healthy fecal microbiota donor, and both trials used patients with melanoma and patients with a durable response to anti-PD1 therapy as donors.
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The first trial
Ten patients with advanced melanoma were treated with antibiotics (6 of whom had previously been positive for ICB) and underwent colonoscopy. The 10 individuals had FMT done with the donor being one of two donors who responded to anti-PD1 therapy, followed by repeated FMT and anti-PD1 therapy in capsule form.
● One complete response and two partial responses in 5 patients who received transplantation from donor 1;
● There was no response in five patients who received a transplant from donor 2.
The microbiota of both donors contained microbiota that favored the response to anti-PD1 therapy, with donor 1 being more enriched in Clostridium and Actinomycetes. After FMT, microbial composition changes at the donor 1 receptor were more consistent than at the donor 2 receptor, and the expression of inflammatory and antigen presentation signatures in the human fecal transcriptome increased. After treatment, three responding patients exhibited more significant tumor rejection, characterized by a type I interferon response and monocyte, DC, NK cell, and T cell infiltration.
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The second trial
Fifteen melanoma patients with primary non-response to anti-PD1 therapy received 1 of 6 donors who responded to anti-PD1 therapy after colon wash (without antibiotic treatment), followed by continuous anti-PD1 therapy; One patient was in complete remission, two patients were in partial remission, and three patients were stable for more than 18 months.
What happened to the microflora of these patients who responded well?
In patients who respond well, the fecal microbiota after FMT becomes more donor-like, and IgG antibodies against the donor flora are more significantly induced. The abundance of beneficial bacteria, such as Trichaleae, Ruminococcaceae, and Bifidobacteria, increased, and the harmful bacteria, such as Bacteroidetes, decreased.
What has changed in other metrics?
In the blood of these responding patients, IL-8 levels decreased, while CXCR13 and IL-21 levels increased, suggesting that T follicle helper cells (TFHs) were responding.
The levels of primary and secondary bile acids, as well as the products of degradation of benzoates, which are markers of microbiota diversity, the presence of certain microflora associated with response to anti-PD1 treatments, are increased.
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Despite the small size and single-arm trial, the overall clinical response rate of 36% in these two pilot studies was higher than that of other combination regimens in patients treated with refractory anti-PD-1 therapy, with no additional serious side effects.
The microflora was effectively colonized after FMT, and the disturbance lasted for more than 1 year
Overall, FMT with a single colonoscopy can interfere with microbiota composition for more than 1 year, even without antibiotic conditioning. Metagenomic analysis has shown that most bacterial genera (and microbial genes) present in the donor but not in the recipient patient can be effectively and persistently colonized unless the recipient is treated with antibiotics.
Is there a possible inconsistency between donor strain colonization and treatment efficacy?
In fact, the composition of the microbiota after FMT reflects not only the colonization of donor-specific flora, but also the changes in intestinal ecology caused by FMT, altering the abundance of different microbiota from donors or recipients.
For melanoma patients who do not respond to anti-PD1 therapy, FMT may only respond to continued anti-PD1 therapy if the patient has an immune response to the tumor but is adversely affected by immunosuppression or microbial composition, resulting in a lack of an immune-boosting microenvironment. FMT can correct this unfavorable microbial composition.
Autologous FMT, rebuilding gut microbiota
Donors can provide a healthier and more diverse microbiota, rebuilding the diversity of the recipient microbiota. However, the risk of transfer of pathogens or antibiotic-resistant pathogens into immunosuppressive receptors also justifies the storage of the patient's own microbiota.
Patients who received autologous FMT had higher numbers of each leukocyte lineage, suggesting that FMT was advantageous. Faecaliberium, Ruminococcus, and Akkermansia are causally associated with increased leukocyte count, and are reconstituted by autologous FMT.
The reasons for resistance to anti-PD1 therapy in cancer patients vary, which may lead to failure of FMT therapy
The reasons include:
1) Unable to respond to the tumor regardless of microbiota composition due to immunosuppression or possible lack of neoantigens in the tumor
2) FMT donors may lack the microbiota needed to respond to anti-PD4 treatment
3) Due to the incompatibility of the donor-recipient microbiota, FMT cannot perturb the microbiota sufficiently
4) The delivery method and frequency of FMT mode may not be optimal
Future developments of FMT in cancer immunotherapy
There is a need to focus on evaluating the best regimen for patient conditioning and microbiota transfer, and identifying patients and suitable donors who are most likely to benefit from FMT.
A number of planned and ongoing trials will determine whether FMT is a routine treatment for patients who do not respond to ICB by evaluating the effectiveness of FMT in different tumor types and modulating the composition of the gut microbiota by comparing or combining FMT with other methods such as probiotics, diet, and prebiotics.
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Probiotics
Probiotic preparations contain anti-inflammatory and mucosal protective flora, such as lactobacilli and bifidobacteria, which are used to prevent toxicity caused by chemotherapy and radiotherapy.
Both clinical and mouse studies have identified bacteria that may become resistant to specific opportunistic infections, as well as potential probiotics that may correct microbiota imbalances.
Lactobacillus spp.: Inhibits tumor growth and improves response to ICIs
The alleviating effects of Lactobacillus rhamnosus, Lactobacillus acidophilus, and Lactobacillus fermentum on colon cancer development have been demonstrated in mouse models.
Lactobacillus rhamnosus GG stimulates type I interferons through the cGAS/STING signaling pathway, thereby improving the response to ICIs.
Lactic acid bacteria (LAB) are effective in reducing the occurrence of colorectal cancer, which may be attributed to the reduction of inflammatory factors. In addition, LAB also affects the gut microbiome, which is characterized by a decrease in the abundance of bacteroides. Therefore, LAB is beneficial in inhibiting the occurrence and progression of cancer.
Lactobacillus reuteri can promote the renewal and repair of intestinal epithelium and stimulate host immunity. It can convert intraepithelial CD4+ T cells into CD4+CD8αα double-positive intraepithelial lymphocytes, thereby alleviating inflammatory bowel disease and preventing the occurrence of some gastrointestinal cancers.
The ability of Lactobacillus reuteri to inhibit ICI-associated colitis is associated with a decrease in group 3 congenital lymphocyte distribution.
Lactobacillus reuteri inhibits the growth of melanoma, liver cancer, and colorectal cancer by producing three tryptophan degradation products:
- 吲哚-3-乳酸酸（ILA, I3L）
- 吲哚-3-醛(I3A)
- 6-甲酰吲哚[3,2-b]咔唑(Ficz)
Bifidobacterium: Enhances anti-PDL1 efficacy
For mice without specific pathogens or microbiota depletion, administration of various microbiota associated with the ICB response improves treatment response.
To validate Bifidobacterium spp. to support anti-PDL1 therapy in mice, administration of over-the-counter commercial probiotic formulations containing four Bifidobacterium strains improved response to anti-PDL1 therapy. Bifidobacteria also increased in patients who responded to anti-PD1 therapy.
Only some strains of Bifidobacterium are able to work synergistically with anti-PD1 treatments in mice. These synergistic strains express genes involved in the synthesis of peptidoglycan pathways, suggesting that they contribute to the production of immunostimulatory molecules.
Faecalibaculum rodentium: 抑制肿瘤生长
F. rodentium and Holdemanella biformis (human homologs) are missing or lost during tumorigenesis, both of which can produce short-chain fatty acids that control tumor cell proliferation and protein acetylation by inhibiting calcineurin and NFATc3 activation.
When F. rodentium is applied to ApcMin/+ mice, colonic adenomatous polyp (APC) gene mutations occur in more than 80% of colorectal cancers, or treatment with azomethane and dextran sodium sulfate can attenuate tumor growth in mice. Similarly, in the ApcMin/+ model, H. biformis appears to be similar to F. rodentium in inhibiting tumor growth via butyrate. Therefore, H.biformis can be applied to the design of cancer treatment.
Streptococcus thermophilus: secretes β-galactosidase, which releases folic acid
Streptococcus thermophiles is a powerful probiotic with digestive and immune benefits that is often depleted in colorectal cancer patients. More importantly, Streptococcus thermophilus has an inhibitory effect on tumorigenesis.
Specifically, oral administration of Streptococcus thermophilus in colorectal cancer mice will significantly reduce tumor formation. β-galactosidase, secreted by Streptococcus thermophilus, is an active ingredient that inhibits the growth of colorectal cancer; β-galactosidase can increase the abundance of two other probiotics, Lactobacillus and Bifidobacteria, suggesting a synergistic effect.
Streptococcus thermophilus affects tumor growth by releasing folic acid. Folic acid is a major dietary element that plays an important role in cellular metabolism and DNA replication, repair, methylation, and nucleotide synthesis. Studies have shown that folate deficiency is fairly prevalent in humans, and folic acid released by Streptococcus thermophilus may be associated with tumor suppression. In addition, Streptococcus thermophilus has an effect on lymphocyte characteristics, severity of colitis, and regulatory T cell responses.
Escherichia coli Nissle 1917: Fewer complications
The E. coli Nissle 1917 strain can modulate intestinal barrier epithelial function, alleviate intestinal dysbiosis, and ultimately reduce intestinal complications caused by irinotecan.
Clostridium butyricum 588 strain: improves patient survival after anti-PD1 therapy
In contrast, in a retrospective analysis, a single probiotic formulation, widely used in Japan and China for the treatment of Clostridium butyricum (CBM) strain 588 with dysbiosis associated with gastrointestinal pathology, significantly improved objective response, PFS, and overall survival in small cell lung cancer cancer patients receiving anti-PD1 therapy. Clostridium butyricum improves microbiosis by increasing lactobacilli and bifidobacteria.
However, a randomized trial of patients with renal cell carcinoma treated with a combination ICB confirmed an improved clinical response in patients treated with Clostridium butyricum but failed to detect an increase in Bifidobacteria.
A combination of multiple bacteria, the effect is 1+1>2
While a single probiotic strain shows promise, the bacterial community may be better at maintaining the ecological balance within the gut microbiota. In both human and mouse species, certain species of Clostridium have been linked to drug resistance to colon cancer.
Mice are administered orally to the following four strains of Clostridium:
- Roseburia intestinalis
- Eubacterium hallii
- Faecalibacterium prausnitzii
- Anaerostipes cacae
Induced the accumulation of activated CD8+ T cells within the tumor and successfully treated chemically induced colon cancer and transplantable colon cancer.
The complex, as a stand-alone treatment, as well as a single species, is more effective than anti-PD1 treatment alone in mice. All four strains produce short-chain fatty acids, including butyrate; However, their immunostimulatory effect is independent of butyrate.
Another approach to the identification of immune-activated bacterial communities involves the identification of a rare human commensal strain that can activate IFNγ-producing CD8+ T cells in the gut of mice. A colony of 11 species remains resistant to Listeria monocytogenes infection in germ-free mice and has antitumor effects additive to anti-PD1 treatment. Notably, 7 species of Bacteroides that have no anticancer activity per se do contribute to the total activity of this community, which supports the importance of multispecies bacterial ecology in rebuilding the gut microbiota. Therefore, trials using single strains and combinations are ongoing.
During immunotherapy, probiotics should also be taken with caution
Melanoma patients who took over-the-counter probiotics did not improve their response to anti-PD1 treatment compared to those who did not take probiotics, but rather declined.
These results, coupled with the heterogeneous nature of the formulations of commercial probiotics and the lack of stringent quality standards for ingredients and viability, suggest that caution should be exercised when using these products during immunotherapy.
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Drink
Changes in diet can rapidly alter the composition of the gut microbiota, as well as the production of bacterial metabolites derived from food fermentation, with metabolic and immune consequences.
Different dietary strategies, including caloric restriction, intermittent fasting, simulated fasting diets, high-fiber diets, ketogenic diets, fermented foods, have all been proposed or tested in mice or patients to improve the treatment of cancer, at least in some cases, shown to affect immunity by altering the composition of the gut microbiota.
In the T cell adoptive transfer model, dietary caloric restriction in mice promoted the accumulation of memory T cells in the bone marrow and enhanced T cell immunity to bacterial infections and tumors.
The fermented food diet continues to increase the diversity of the microbiome and alter its composition through an overall anti-inflammatory effect.
The effect of the high-fiber diet on the diversity and composition of the microbiome was more modest, with no significant effect on the frequency of immune cells and the expression of cytokines, but had different effects on endogenous signaling in immune cells, with an increase in endogenous signaling in one group of individuals with a high inflammatory index and a decrease in the inflammatory index in the other two groups of individuals with a low inflammatory index profile.
Diet may affect anti-cancer immunity by altering the microbiota
Melanoma patients receiving anti-PD1 therapy had better response and survival on a fiber-adequate diet of more than 20 g/day, with an increase in fiber per 5 g equivalent to a 30% reduction in the risk of progression or death.
Consistent with another study, the human gut microbiota with different fiber intakes did not show significant changes in composition or bacterial richness, but the removal of most of the fiber content from mouse food resulted in rapid changes in the microbiota, with a decrease in Bifidobacterium spp. and an increase in AKK bacteria. Mice on a low-fiber diet responded poorly to anti-PD1 cancer treatment, with similar clinical outcomes. Thus, in germ-free mice, the high- and low-fiber diets did not affect the response to anti-PD1 treatment, suggesting that the diet may affect anti-cancer immunity by altering the microbiota.
Cross-species network analysis showed that the high-fiber diet of mice maintained effective tumor immunity by expanding the Ruminococcus genus of fermented fiber. Rumen coccus genus induces T cell activation and tumor infiltration, including CD8+ and CD4+ T cells expressing inducible T cell costimulatory factor (ICOS).
A simulated fasting diet (FMD) may reduce toxicity in cancer patients and improve their response to chemotherapy, but most studies of this dietary intervention have not addressed the role of altered gut microbiota.
The positive effects of fasting on chemotherapy are manifested in four ways:
- Synergistic effect with pharmacological interventions
- Enhances host immunity
- Enhance the sensitivity of tumor tissues or cells to chemotherapy
- Reduces side effects such as headaches, blood toxicity, weight loss
Metformin, vitamin C, platinum, and trametinib in combination with fasting can enhance the effects of chemotherapy.
For triple-negative breast cancer, a simulated fasting diet activates the starvation escape pathway in cancer cells and reduces surface markers in cancer stem cells, leading to increased recognition of chemotherapeutic agents.
The ketogenic diet enhances the antitumor effects of anti-PD1 therapy in mice by inducing T-cell cancer immunity mediated by the ketone body 3-hydroxybutyrate. In mice and humans, although the effect of diet on tumor immunity was mediated by an increase in 3-hydroxybutyrate and did not depend on alterations in the gut microbiota, although the anti-cancer effect of a low-carbohydrate diet was consistent in increasing the abundance of bacterial species such as Eisenbergiella massiliensis.
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Prebiotics
Inulin and pectin are soluble fibers found naturally in many vegetables and fruits that cannot be digested by gastrointestinal enzymes but can be fermented by bacteria. Thus, they exert the role of prebiotics by altering the composition of the gut microbiota, strengthening the mucosal barrier, enhancing epithelial integrity, and activating or inhibiting innate immune cells.
Inulin → produce short-chain fatty acid bacteria→ enhance anti-PD1 efficacy
In mice, oral treatment with inulin gel increases the abundance of short-chain fatty acid-producing bacteria and enhances the antitumor activity of anti-PD1 therapy.
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Pectin enhances anti-tumor immunity by two distinct mechanisms.
Pectin → produce short-chain fatty acid bacteria→ enhance anti-PD1 efficacy
Pectin feeding enhances the response of mice transplanted with fecal microbiota from cancer patients to anti-PD1 treatment, activates tumor immunity by butyrate through expanded fiber feeding and production of short-chain fatty acids Lachnospiraceae and Ruminococceae.
Pectin → AKK bacteria → activate STING→ improve tumor immunity
Pectin feeding can also improve tumor immunity by causing the expansion of AKK bacteria, which produces cyclic adenosine diphosphate (cyclic-di-AMP) and activates STING; The resulting type I interferon-dependent immuno-tumor microenvironment characterization is associated with immune-mediated tumor resistance in mice and melanoma patients.
Camu camu → increases diversity, beneficial bacteria → enhances anti-PD1 efficacy
In mouse studies, the oral administration of the polyphenol Castalagin (a hydrolyzable tannin) isolated from camu camu had anti-tumor effects and enhanced anti-PD1 therapeutic effects in mice by increasing the diversity of the gut microbiota and altering its composition by increasing the composition of bacteria that are expected to be beneficial against PD1 treatment, such as Ruminomyceae, Oscillospiraceae and AKK.
Chestnut ellagin reprograms the tumor immune microenvironment by influencing gut microbiota composition, and to some extent promotes anti-cancer responses by directly binding to commensal bacteria such as Ruminococcus bromii, which may help expand the variety of this and other beneficial bacteria, promoting anti-PD1 treatment responses. This suggests that chestnut ellagin and other traditional food additives or their components may be sources of prebiotics to improve immunotherapy responsiveness by targeting the microbiota.
Ginseng polysaccharides → increase valeric acid → enhance anti-PD1 efficacy
Ginseng polysaccharides, a prebiotic derived from ginseng, can enhance cancer response to PD1 inhibitors by decreasing the ratio of kynurenine/tryptophan and increasing the microbial metabolite valeric acid, thereby promoting the induction of Teff cells and regulating the inhibition of T cells.
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Conclusion
The gut microbiota can influence tumor development and treatment efficacy through a variety of mechanisms in cancer treatment.
Studies have shown that the gut microbiota may be a prognostic and predictive marker for a variety of cancer types. The gut microbiota is expected to enhance anti-cancer power, improve the efficacy of radiotherapy and chemotherapy, and enhance the efficacy of immunotherapy to reduce mortality and improve quality of life. Preliminary clinical trials have shown that FMT in patients who respond to anti-PD1 therapy can overcome primary and acquired resistance to ICB therapy, demonstrating that it can target the microbiota to enhance treatment response.
However, there are many obstacles and limitations in the advancement of these clinical treatment studies. Individual biological differences may hinder the application of microbial strategies. Challenges in this area include the need for prospective validation in different cancer types, stages, geographic regions, age, genetics, gender, lifestyle, concomitant diseases, treatments, and comorbidities. Caution should also be exercised in generalizing the results from mice to humans.
While there are challenges, solutions are being studied. Advances have been made in the application of machine learning methods to analyze the composition of the gut microbiota of patients that take into account different populations and geographical differences, which may soon make the gut microbiota a reliable biomarker for predicting a patient's response to treatment, allowing for personalized selection of the most appropriate treatment.
Combining the gut microbiota with other biomarkers that independently regulate the efficacy of ICIs, such as PD-L1, TMB, IL-8, or certain metabolites, may improve the ability to predict the effect of immunotherapy.
Future clinical advances require more precise identification of causal relationships between bacterial taxa that have positive and negative effects on cancer treatment, as well as an understanding of their mechanisms of action, and therefore require more extensive trials.
The improved bacteria may be used as anti-cancer therapeutics or even modified into guided "microrobots" for drug delivery.
Overall, developments in this area offer new treatment options and hope for cancer patients, but at the same time, they need to be carefully evaluated and monitored to ensure safety and efficacy.
The importance and potential of the gut microbiota for the development of new anti-cancer strategies is worth emphasizing, and there is a need to explore a holistic approach system that incorporates microbial modulatory therapies into current cancer management. In the future, we are expected to achieve more precise and personalized gut microbiota regulation strategies, which will bring greater breakthroughs and progress to cancer treatment.
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