New findings in the fight against cancer: this bacterial product, or breast cancer "buster"

Breast cancer is one of the common malignant tumors that threaten women's health, and triple-negative breast cancer is known as the "king of breast cancer" due to the lack of effective therapeutic targets, which has a high risk of recurrence and a poor prognosis. Immunotherapy is a promising cancer treatment that has good efficacy for non-small cell lung cancer and melanoma, but is only useful for a small percentage of triple-negative breast cancer patients. Therefore, paying attention to the latest research directions of tumor immunotherapy, such as the synergistic anti-cancer effect of bacteria in vivo, can provide a new treatment strategy for immunotherapy for triple-negative breast cancer.

"Pink Killer" – breast cancer

Breast cancer is the most common malignancy in women. Global cancer statistics for 2022 show that about 306,000 women have been diagnosed with breast cancer and 72,000 women have died of breast cancer [1].

Figure 1 Focus on breast cancer Imageworm creativity

Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer that does not express the estrogen receptor (ER), progestin receptor (PR), or human epidermal growth factor receptor 2 (HER-2), which is more aggressive, has higher metastasis potential, is more prone to recurrence, and has a worse prognosis than ordinary breast cancer.

Moreover, TNBC has limited treatment options compared to other types of breast cancer, mainly because the expression of ER, PR, and HER2 is negative, making specific endocrine therapy and targeted therapy ineffective. Therefore, chemotherapy is currently the mainstay of treatment for TNBC [2].

Clinical outcomes for immunotherapy for TNBC are not ideal, so it is urgent to develop more effective treatments for patients with TNBC. With our discovery of molecular biomarkers for TNBC, treatments for TNBC are shifting to biological approaches. However, due to the high heterogeneity of TNBC between and within tumors, discovering new therapeutic targets and performing targeted therapies is very challenging [2]. Studies have shown that TNBC can be divided into four subtypes: immunomodulatory (IM), luminal androgen receptor (LAR), basal-like immunosuppression (BLIS), and mesenchymal-like (MES). Compared with other subtypes, im subtypes are characterized by the enrichment of immune-activating cells and immunostimulants in the microenvironment, suggesting that patients with IM subtype TNBC may respond better to immunotherapy [3]. Therefore, there is an urgent need to identify factors that can modulate the TNBC microenvironment and promote anti-tumor immunity.

New discovery: Bacterial products can help fight cancer

There are a large number of bacteria living in the human body, under normal circumstances, these bacteria symbiosis with the human body and play an important role in maintaining human health, such bacteria are also called symbiotic bacteria. Studies have shown that symbiotic bacterial groups also exist in human breast tissue.

In early March 2022, the research group of Shao Zhimin, Jiang Yizhou and Zhao Chao of Fudan University published "The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer" in Cell Metabolism.[4]

Figure 2 https://doi.org/10.1016/j.cmet.2022.02.010

In this study, the researchers focused on the anti-cancer effects of co-existing bacteria in breast tissue. Multi-omics analysis of one group of patients with TNBC (n = 360) found that the proportion of Clostridium species in the breast microenvironment of immunomodulatory subtype (IM) patients was significantly higher than that of other subtypes, and that the associated metabolite N-oxide trimethylamine (TMAO) was associated with an increase in immunotherapy efficacy in TNBC. Final note: TMAO, a metabolite of bacteria, inhibits tumor growth, and TMAO precursor choline can enhance TNBC's response to immunotherapy, suggesting that high choline protein, fish meat, and beef help improve the efficacy of immunotherapy for triple-negative breast cancer.

How bacteria-produced TMAO helps fight cancer

The researchers mainly divided it into 5 steps, indicating that the TMAO produced by bacteria has an anti-cancer effect.

Figure 3 https://doi.org/10.1016/j.cmet.2022.02.010

Step 1: Elucidating the multi-omics changes in the TNBC immune-activated microenvironment, screening for a positive correlation between the Clostridium-dependent metabolite TMAO and the immuno-activated microenvironment. First, the researchers found that bacteria colonized in the tumor tissues of TNBC patients, and Clostridium spp. was more abundant in the IM subtype, and secondly, the researchers further studied the relationship between the metabolite TMAO and the commensal bacteria, and found that there was a positive correlation between TMAO and the immune-activated microenvironment.

Step 2: Illustrate that TMAO inhibits characteristic cells that are dependent on tumor growth, and it is found that TMAO inhibits tumor growth by activating CD8+ T cell-mediated anti-tumor immunopathy. Due to the early stage in the pathway analysis, it was found that the T cell-related pathways were enriched in the high TMAO subgroup. Thus, building mouse models and injecting TMAO into mice within tumors was found to significantly promote infiltration of CD8+ T cells and M1 macrophages, enhancing the function of CD8+ T cells. These results suggest that CD8+ T cells play a vital role in TMAO-mediated host anti-tumor immunity.

Step 3: Investigate the direct killing effect of TMAO on tumor cells and molecular pathways, and verify that TMAO induces GSDME (a precursor of a pore-forming protein that can convert non-inflammatory apoptosis into coke death) mediated coke death of tumor cells, requiring the participation of the PERK pathway. After TMAO treatment, the cleaved caspase 3 and GSDME, two key proteins involved in coke death, were upregulated, indicating that TMAO induces cytofoulospheriosis in tumor cells, and by knocking down the expression of GSDME, indicating that TMAO activates anti-tumor immunity in TNBC by inducing GSDME-mediated coke death of tumor cells. Further cell tests and mouse models show that the microbial metabolite TMAO activates PERK-mediated ER stress, leading to activation of caspase 3 in tumor cells and GSDME-mediated cellular focus death.

Step 4: Verify the relationship between clinical indicators in patients with TNBC and plasma TMAO expression. Plasma TMAO concentrations were positively correlated with optimal response to immunotherapy, and patients with high plasma TMAO concentrations had longer progression-free survival and better responses to immunotherapy than patients with low plasma TMAO concentrations. This indicates that high plasma TMAO expression is associated with an increase in the effect of immunotherapy in patients with advanced TNBC.

Step 5: In a mouse model, TMAO and TMAO precursor choline are administered to detect their anti-tumor effect.

In the mouse tumor model of TNBC, intraperitoneal co-injection of TMAO and anti-PD-1 antibodies effectively activated anti-tumor immunity and inhibited tumor growth, indicating that TMAO's systematic administration inhibits the growth of TNBC by activating anti-tumor immunity, and that choline-rich diets can upregulate TMAO in mouse tumor tissues and inhibit tumor growth by enhancing anti-tumor immunity.

The synergistic anti-cancer effect of bacteria in vivo can provide a new treatment strategy for immunotherapy for triple-negative breast cancer, bringing good news to patients.

Author: S.Yi

Source: Frontline of Cancer in the Health Community

Resources

[1] Jemal A , Bray F , Center M M . Global cancer statistics, 2012. [J]. Ca A Cancer Journal for Clinicians, 2013, 65(2):87-108.

[2] Yin L , Duan J J , Bian X W , et al. Triple-negative breast cancer molecular subtyping and treatment progress[J]. Breast cancer research: BCR, 2020, 22(1).

[3] Yi-Zhou Jiang , Ding Ma , et al. Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies[J]. Cancer Cell, 2019. Mar 18;35(3):428-440.e5.

[4] Hai Wang , Xingyu Rong , et al. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer[J]. Cell Metab. 2022 Mar 8; S1550-4131(22)00054-7.