One of the hateful things about cancer cells is that they "bring bad" immune cells in the human body and turn them into accomplices to evil, so when you see the prefix "tumor-related", Singularity Cake has a feeling of hating iron but not steel.
Take macrophages as an example, they are supposed to be the main force to engulf and eliminate various external enemies in the human body, but once they reach the tumor microenvironment and become tumor-associated macrophages (TAMs), they immediately begin to promote cancer progression in various ways, and will also affect the effect of anti-cancer treatment, which can be described in four words:
Bad things are done.
Cancer-promoting and immunosuppressive mechanisms of TAMs
However, from another point of view, since macrophages may be dragged down by cancer cells, it means that they still have strong plasticity.
It is precisely based on these considerations that a variety of innovative anti-cancer therapies are being developed around macrophages, such as those that enhance macrophage recruitment, regulate the polarization of TAMs, activate or inhibit specific cytokines/chemokines, and even add chimeric antigen receptors (CARs) to macrophages......
In a recent issue of Nature Reviews Drug Discovery, four experts from the Humanitas University Hospital in Milan, Italy, conducted an in-depth review of the significance of macrophages as targets and tools in cancer therapy [1]. How are macrophage-based treatment strategies progressing? Let's take a look!
Diversity of TAMs and their impact on prognosis
The current study suggests that TAMs in the tumor microenvironment are composed of two parts: one is from tissue-resident macrophages that exist in the embryonic stage, which create a cancer-friendly microenvironment in the early stage of cancer, and the typical role of microglia (macrophages in the central nervous system) on glioma is typical; The other part of the main TAMs that arrived later were derived from bone marrow-derived mononuclear precursor cells.
After being recruited to the tumor site, TAMs will enter a type 2 inflammatory response state that inhibits the anti-tumor immune response, that is, polarized to the M2 phenotype, under the influence of cytokines such as TGF-β, CCL2, IL-1/4, and even microorganisms in tumor tissues, and can also be subdivided into many subpopulations with different functions and gene expressions.
Possible immunosuppressive mechanisms of TAMs
For example, in colorectal cancer, TAMs invasion is mostly associated with a better prognosis, but in colorectal cancer liver metastases, the conclusion must be reversed [2-3].
The role of TAMs in traditional anti-cancer therapy
Due to the important regulatory role of TAMs in anti-tumor immune response, chemotherapy, radiotherapy, endocrine therapy, anti-angiogenic therapy and even immunotherapy will be affected by TAMs to varying degrees, but these treatment methods will also act on TAMs in turn, presenting a pattern of both cooperation and struggle.
For example, the effectiveness of various monoclonal antibody drugs is often inseparable from antibody-dependent cellular phagocytosis (ADCP); TAMs-activated signaling pathways may also limit the efficacy of chemotherapy drugs and even participate in mediating drug resistance. At the same time, TAMs also have a key impact on tumor neovascularization, which will directly affect the efficacy of anti-angiogenic drugs.
Gemcitabine, which is commonly used in pancreatic cancer chemotherapy, fluorouracil, a veteran of colorectal cancer chemotherapy, and classical platinum-containing doublet chemotherapy can polarize TAMs from M2 phenotype to M1 phenotype, which is conducive to anti-tumor immunity. The new lung cancer chemotherapy drug lurbinectedin, which has been approved by the FDA, can directly induce apoptosis of TAMs.
In a review published in Nature Review Clinical Oncology in 2017, the Italian experts who wrote this article used the "yin and yang poles" to describe the impact of TAMs on traditional treatment methods such as chemotherapy and radiotherapy, but today, five years later, everyone is more concerned about the "love-hate relationship" between TAMs and immunotherapy.
The so-called "yin and yang poles"
Relationship of TAMs to existing immunotherapy
Myelomonocytic cells, including macrophages, are the main "black hands" of tumor microenvironment-mediated immunosuppression, because such cells often have ligands for immune checkpoints such as PD-L1/L2 and B7-1/2 on the surface, and macrophages may also express the corresponding receptors of negative regulators of T cells and NK cells, such as V-domain immunoglobulin inhibitory factor (VISTA) of T cell activation, thereby inhibiting the anti-tumor immune response.
Studies in tumors such as triple-negative breast cancer and kidney cancer have confirmed that macrophages may mediate primary/secondary resistance to immune checkpoint inhibitors by inducing T cell apoptosis and inhibiting T cell proliferation [4-5]. However, instead of directly killing macrophages, another way of thinking is also worth trying.
The main ideas and research progress of transforming TAMs
Due to the plasticity of TAMs, appropriate treatment methods are still expected to make TAMs change from evil to right and become a boost for immunotherapy, and the current exploration mainly focuses on M2 phenotype TAMs, which is carried out in the following directions:
The main exploration directions for TAMs reprogramming
1) Targeting the recruitment and accumulation of TAMs
A variety of chemokines, such as macrophage colony-stimulating factor (CSF1) and CCL2, have an important impact on the specific functions of monocyte recruitment and performance in the tumor microenvironment, but monoclonal antibody drugs targeting the corresponding receptors of CSF1/CCL2 have failed to achieve therapeutic benefit in clinical studies, and most of the development has been terminated. It has been suggested that specific subsets of TAMs should be considered, rather than targeting all TAMs in general.
2) Complement system
The leptin signaling pathway, C3a, C5a and other components in the complement system have been shown to be related to the recruitment of TAMs to the tumor microenvironment and the exertion of immunosuppressive functions, and preclinical studies have shown that there is a synergy between therapeutic drugs that block complement components and PD-1 inhibitors [6], and follow-up clinical studies are advancing.
3) inflammasomes and IL-1
Interleukin-1 (IL-1) promotes cancer by enhancing the immunosuppressive function of TAMs, and preclinical studies have shown that targeting IL-1β counteracts this cancer-promoting effect [7], which may explain the anticancer effects of canakinumab. In addition to directly targeting IL-1β, inhibition of inflammasomes such as NLRP3 further upstream of the immune pathway may also weaken the immunosuppressive function of TAMs, but related clinical studies have been shelved due to the impact of the epidemic.
4) mRNA and miRNA
Attempts have been made to inject mRNAs carrying specific transcription factors into tumor sites to reprogram TAMs at the gene level, thereby reversing the suppression of the immune microenvironment [8]. Based on miRNA, targets such as miR-155, which has an important impact on the differentiation and polarization of TAMs, were selected, and also showed tumor suppression in preclinical studies.
Making TAMs "strong again"
In addition to reprogramming TAMs, there are multiple strategies to reactivate the anti-cancer function of TAMs.
Uses signaling molecules to activate macrophages
The Italian experts mainly mentioned the following three types of activation signals:
1）CD40
After CD40 binds to its ligand CD40L, it can activate the positive feedback pathway, activate the production of tumor necrosis factor (TNF) and reactive oxygen species, thereby further positively regulating the participation of TAMs in anti-tumor immune responses. Preclinical studies have shown that CD40-targeting monoclonal antibodies can "re-educate" immunosuppressive TAMs into cytotoxic phenotypes, and related drugs are in the early clinical research stage.
2）Toll样受体（TLRs）
TLR agonists have attracted much attention in a variety of diseases in recent years due to their ability to activate immune responses, and the immune responses activated by TLR agonists are often regulated by TAMs. From preclinical studies, TLR agonists can also reprogram TAMs.
3）STING
The STING pathway regulates a broad range of immune responses, so the effect on TAMs is non-specific.
Targeting macrophage checkpoints
Similar to various T cells, the function of TAMs is regulated by many checkpoints, such as signal regulatory proteins α (SIRPα), sialic acid-binding immunoglobulin-like lectins (SIGLECs), leukocyte immunoglobulin-like receptor B (LILRB), CD163 and other pro-inflammatory "scavenger receptors", as well as the "don't eat me" signaling molecule CD47 (binding to SIRPα on macrophages) on the surface of normal cells.
In addition, there are checkpoints on the surface of macrophages whose expression is not limited to the mononuclear cell lines of the nuclea, such as PD-1, TREM2, and PSGL1, and cancer cells often take advantage of the weakness to use these inhibitory checkpoints to evade anti-tumor immunity.
Inhibitory receptors present on the surface of immune checkpoints or other cell surfaces on the surface of macrophages
From the early research, targeting CD47/SIRPα and other pathways can not only activate the phagocytosis of TAMs, cooperate with existing PD-1/L1 inhibitors, but also achieve synergies with classical targeted drugs such as rituximab and trastuzumab by enhancing the ADCP effect [9], and it is expected that these explorations will be translated into results in clinical research.
Start with the metabolism of TAMs
Changes in the function of TAMs and adaptation to hypoxia and lack of nutrients after entering the tumor microenvironment will inevitably lead to the reprogramming of TAMs to the metabolic process of lipids, amino acids and other substances, and drugs such as HDAC inhibitors, IDO1 inhibitors, and metformin (inhibition of glycolysis) may have room to play a role in this regard.
Macrophage-based cellular immunotherapy
Macrophage-based cellular immunotherapy has a unique advantage - mononuclear phagocytic cells circulating in the blood will continue to be recruited to the tumor site and become a steady stream of reinforcements, so CAR-M therapy built with chimeric antigen receptor (CAR) technology is also being explored in the early stage, and the modified macrophages can maintain the anti-tumor M1 phenotype and effectively kill cancer cells without fear of the immunosuppressive microenvironment.
Mechanism of action of CAR-M therapy
summary
Macrophages play an extremely important role in the occurrence and development of cancer, and the efficacy of various treatment methods from chemotherapy to immunotherapy will also be affected by macrophages, but due to the complexity of the mechanisms and pathways involved, most of the current therapeutic explorations are still in their infancy, and they need to be deeply explored from multiple perspectives such as functional phenotype, cell metabolism, and immune checkpoints, so as to achieve the goal of using macrophages to treat cancer and even prevent cancer.
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Bibliography:
1.Mantovani A, Allavena P, Marchesi F, et al. Macrophages as tools and targets in cancer therapy[J]. Nature Reviews Drug Discovery, 2022.
2.Forssell J, Öberg A, Henriksson M L, et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer[J]. Clinical Cancer Research, 2007, 13(5): 1472-1479.
3.Donadon M, Torzilli G, Cortese N, et al. Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis[J]. Journal of Experimental Medicine, 2020, 217(11): e20191847.
4.Yu J, Green M D, Li S, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination[J]. Nature Medicine, 2021, 27(1): 152-164.
5.Chow A, Schad S, Green M D, et al. Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity[J]. Cancer Cell, 2021, 39(7): 973-988. e9.
6.Ajona D, Ortiz-Espinosa S, Moreno H, et al. A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and MetastasisAnti–PD-1 and Anti-C5a Combined Immunotherapy in Lung Cancer[J]. Cancer Discovery, 2017, 7(7): 694-703.
7.Aggen D H, Ager C R, Obradovic A Z, et al. Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional AnalysesTargeting IL1 Beta for Kidney Cancer Immunotherapy[J]. Clinical Cancer Research, 2021, 27(2): 608-621.
8.Zhang F, Parayath N N, Ene C I, et al. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers[J]. Nature Communications, 2019, 10(1): 1-16.
9.Ring N G, Herndler-Brandstetter D, Weiskopf K, et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity[J]. Proceedings of the National Academy of Sciences, 2017, 114(49): E10578-E10585.