November 28, 2021

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How does the tumor micro-environment affect immunotherapy?

How does the tumor micro-environment affect immunotherapy?

How does the tumor micro-environment affect immunotherapy?


The efficacy of tumor immunotherapy depends to a large extent on the tumor microenvironment, especially the tumor immune microenvironment. New research shows that microorganisms exist in tumor cells and immune cells, indicating that these microorganisms can affect the state of the tumor immune microenvironment.

Tumor microbe microenvironment plays a multi-faceted role in tumor immune microenvironment: it may act as immune activator, inhibitor or bystander. Potential mechanisms include:

(I) cancer cells and immune cells present microbial antigens,

(II) microbial antigens mimic tumor antigens,

(III) microbial-induced immunogenic cell death,

(IV) microbes mediated by pattern recognition receptors Auxiliary,

(V) microbial-derived metabolites, and (VI) microbial stimulation of inhibitory checkpoints.

In general, the tumor micro-environment regulates the tumor immune micro-environment, making it a potential target for improving immunotherapy. This is a new field facing major challenges and is worthy of further exploration.

Tumor micro-environment

The human body contains trillions of microorganisms, some of which contribute to carcinogenic or anti-cancer reactions. Microorganisms, such as bacteria, fungi, viruses, and mycoplasma, exist in tumor tissues. Microbial residues such as DNA, RNA, peptides and cell wall components can be observed in cancer cells and tumor-infiltrating immune cells.

Some microbial metabolites, including fatty acids and inosine, can accumulate in tumors and bind to receptors on cancer cells and immune cells. These components play a role in the occurrence, development, metastasis and immune response of tumors.

The microenvironment formed by them is different from the usually mentioned tumor microenvironment, so it can be used as a new type, called “tumor microbial microenvironment” .

How does the tumor micro-environment affect immunotherapy?

The tumor micro-environment has clinical significance. First of all, the intratumoral microbiome has tumor type specificity and subtype specificity, and may be used as a diagnostic tool. For example, the pancreatic cancer microbiome is mainly Proteobacteria; and the colorectal cancer microbiome is mainly Firmicutes and Proteobacteria. Second, the microbiome of tumor tissue is significantly different from that of normal tissue, making it a powerful therapeutic target.

Certain microorganisms accumulate specifically in tumor tissues, and the fact that microorganisms are attracted to tumors enables these microorganisms to be used as precise anti-cancer drug carriers. Third, the tumor microbiome is different in patients with different survival rates, which makes it a potential prognostic tool.

In pancreatic cancer, compared with short-lived patients, the tumor microbiome of long-term surviving patients has higher alpha diversity and features of Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Klaus Bacillus .

The Mechanism of Action of Tumor Microbial Microenvironment

A number of studies have observed the correlation between the microbes in the tumor and the tumor microenvironment. Recent studies have shown that there are multiple mechanisms of tumor microenvironment acting on the tumor microenvironment, including:

(I) cancer cells and immune cells present bacterial peptides,

(II) bacterial antigens mimic tumor antigens

(III) microbial-induced immunogenic cells Death

(IV) auxiliary pattern recognition receptor-mediated signaling pathway

(V) microbial-derived metabolites

(VI) stimulate inhibitory checkpoints.

How does the tumor micro-environment affect immunotherapy?

Microbial antigens may activate anti-tumor T cells

Two key steps are required to successfully induce an adaptive anti-tumor response. The first step is to present tumor antigens by human leukocyte antigen (HLA) to activate CD8+ T cells. The second step is to activate CD8+ T cells to recognize and kill antigen-specific cancer cells. However, cancer cells can hide their antigens from immune cells through a variety of mechanisms.

Bacterial peptides are ubiquitous in melanoma metastasis. They can be presented by HLA molecules on melanoma cells and tumor infiltrating immune cells, proving their potential as tumor-specific antigens. B cells carrying bacterial peptide HLA complexes can activate tumor-infiltrating T cells to secrete IFN-γ in the body. Other bacterial peptides are also ubiquitous in a variety of melanoma patients. In addition, given that bacterial peptides are exogenous, they are related to tumors. Compared with antigens, they are more likely to trigger an immune response.

However, bacterial peptides as tumor-specific antigens still have some problems. First of all, it is not clear whether there are bacterial peptides in normal tissues. If bacterial peptides also appear in normal tissues, these tissues will inevitably be attacked. Secondly, the bacterial peptides presented by cancer cells do not trigger effective anti-cancer immunity in the body, and the underlying cause is still unclear. The interaction between bacterial peptides, cancer cells and immune cells in the body needs further study.

Microbial antigen mimics activation of anti-tumor T cells

Antigen mimicking is a phenomenon in which microorganisms and tumor antigens share similar epitopes. Microbial-specific T cells can recognize and kill cancer cells that express similar epitopes.

Alexandra Snyder and colleagues analyzed tumor neoantigen epitopes in melanoma patients with different prognosis. They found that some tumor neoantigen epitopes are homologous to microbial epitopes, and the higher the homology, the better the clinical prognosis. This finding indicates that antigen mimics exist in tumors and may affect immune responses.

Shin Heng Chiou and colleagues analyzed 770,000 T cell receptor sequences from 178 lung cancer patients. They found that compared with normal tissues, tumor tissues overexpress a protein that cross-reacts with Epstein-Barr virus and E. coli, and this cross-reaction exists in multiple lung cancer samples. In the future, it is necessary to explore the mimics of microbial antigens that exist in various types of tumors. These “simulated antigens” may provide new prospects for cancer treatment.

Microbial induced immunogenic cell death

Immunogenic cell death (ICD) is a form of cell death in which dead cells release antigens and adjuvants to enhance the immune response. It can be triggered by microorganisms. Some researchers have combined the empty envelope of bacteria and oxaliplatin to treat mouse models of advanced colorectal cancer. The combined strategy strongly inhibits tumor growth and prolongs the survival of mice by strengthening ICD.

Oncolytic viruses or bacteria specifically target the tumor microenvironment and dissolve tumor cells, thereby releasing tumor antigens, damage-related molecular patterns, and pathogen-related molecular patterns to recruit peripheral immune cells or restart existing anti-tumor immune cells. At the same time, the microorganism itself can be used as a promising immune adjuvant to promote inflammatory TME, thereby further enhancing anti-tumor immunity.

Auxiliary Pattern Recognition Receptor Regulates TME

Microbial assistance refers to the immunomodulatory effects of pathogen-related molecular patterns derived from microorganisms. Pathogen-related molecular patterns can be sensed by pattern recognition receptors (PRR). Toll-like receptors (TLR) are the most studied subtype of PRR. The microbial activation of TLRs plays a double-edged role in the tumor immune microenvironment.

How does the tumor micro-environment affect immunotherapy?

First of all, microorganisms in tumors drive the formation of immunosuppressive tumor microenvironment through TLR. In a mouse model of pancreatic cancer, microorganisms in the tumor selectively activate TLRs in monocytes to induce M2-like TAM differentiation. The bacterial lipopolysaccharide recognized by TLR4 induces hepatocytes to express CXCL1. CXCL1 is a chemokine that can recruit CXCR2+ polymorphonuclear MDSCs to form an immunosuppressive environment and promote cholangiocarcinoma in mice. Similarly, Fusobacteria recognized by TLR4 up-regulate the IL-6/p-STAT3/c-MYC signaling pathway, leading to M2-like TAM polarization and colorectal cancer progression.

On the other hand, microorganisms in tumors maintain the immunostimulatory tumor microenvironment through TLRs, and therefore act as anticancer agents. In a mouse model of lung cancer, bacterial lipoproteins activate TLR2, and MDSCs are reprogrammed to differentiate into the inflammatory M1 phenotype. In addition, TLR agonists work synergistically with IFN-γ to increase the pro-inflammatory cytokines TNF-α, IL-12p40 and IL-12p70, reduce IL-10, form an inflammatory microenvironment, and activate anti-tumor immune responses.

In general, microorganisms regulate tumor immune microenvironment through PRR, and a specific microorganism can interact with various PRRs at the same time. Therefore, the immunomodulatory effect of microorganisms is the sum of many signal pathways mediated by different PRRs.

Microbial derived metabolites

Microbial metabolites such as short-chain fatty acids (SCFA), bile acids and inosine can enter the blood. Some receptors for microbial-derived metabolites are expressed on cancer cells and tumor-infiltrated immune cells, indicating the potential role of microbial-derived metabolites in the tumor microenvironment.

SCFA is a product of dietary fiber fermented by intestinal anaerobic bacteria. SCFA includes acetic acid, propionic acid and butyric acid. For normal intestinal epithelial cells, SCFAs can inhibit tumor inflammation.

For example, butyrate can increase the levels of IL-10 and retinoic acid in the intestinal microenvironment, thereby promoting the differentiation of naive T cells into regulatory T cells. In addition, it also promotes the proliferation of regulatory T cells, thereby inhibiting pro-tumor inflammation.

Secondary bile acids, such as ω-murocholic acid, down-regulate the secretion of the chemokine CXCL16 in sinusoidal endothelial cells.

Therefore, natural killer T cells recruited by the CXCR6-CXCL16 interaction are reduced. Antibiotics can eliminate microorganisms and reverse the aforementioned effects.

Current studies have shown that bile acids regulate natural killer cells through CXCL16-CXCR6 and play an important role in the occurrence and development of liver cancer.

Stimulus inhibitory checkpoint

Fusobacterium nucleatum inhibits the activity of natural killer cells and cytotoxic T cells through the interaction between Fap2 and TIGIT or the interaction between Fap2 and CEACAM1.

Helicobacter pylori acts on CEACAM1 through its outer membrane protein HopQ to suppress immune cells. In addition to Helicobacter pylori and Fusobacterium nuclear, other bacteria, such as pathogenic Neisseria, can also bind to CEACAM1.

Another checkpoint, CD47, is expressed on the surface of tumor cells. SIRPα is the ligand of CD47 and is expressed on dendritic cells and macrophages. Intratumoral injection of antibiotics eliminated bifidobacteria and reduced the effect of CD47 blockade, indicating that bifidobacteria may be a potential adjuvant for CD47 blockade.

Clinical Application of Tumor Microbial Microenvironment

Three elements are needed to successfully induce an anti-tumor adaptive immune response: antigen, adjuvant and a suitable immune microenvironment. The tumor microbial environment simultaneously affects these three elements, making it a promising combination for the treatment of ICIs.

Clinical strategies for endogenous microbial regulation include antibiotics and probiotics. Exogenous microorganisms regulate microorganisms produced by synthetic biology methods, such as engineered bacteria and oncolytic viruses.

The use of Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer and the use of oncolytic virus talimogenelaherparepvec (T-VEC) to treat advanced melanoma are two examples of successful tumor microbial microenvironment regulation.

How does the tumor micro-environment affect immunotherapy?

Synthetic biology

Microbes have long been used as programmable drug delivery platforms. Recently, microorganisms have been designed to enhance immunotherapy. The study designed a non-pathogenic Escherichia coli strain to load CD47 nano antibody blocker. The strain colonizes the tumor and releases the CD47 nanobody blocker, and then activates tumor-infiltrating T cells to eliminate the tumor.

Another engineered E. coli strain named SYNB1891 also uses a similar strategy. This strain activates the STING pathway in antigen-presenting cells, thereby enhancing the phagocytosis of cancer cells. In addition to adding immunostimulatory microorganisms to tumors, synthetic biology can also remove immunosuppressive microorganisms from tumors.

For example, the complex of specific phage of Fusobacterium nucleatum and silver nanoparticles cleared Fusobacterium nucleus in tumors, reduced myeloid-derived suppressor cells in tumors, and enhanced the efficacy of ICIs.

Antibiotics and immune checkpoint inhibitors

Clinically, the use of antibiotics is negatively correlated with the clinical outcome of ICIs treatment. The impact of antibiotics on immunotherapy can be explained by antibiotic-mediated microbial regulation. On the one hand, antibiotics can cause microbial interference and impair the efficacy of ICIs.

On the other hand, antibiotics can eliminate harmful microorganisms induced by chemotherapy, thereby improving the efficacy of ICIs. Therefore, it is necessary to monitor the changes of microorganisms in preclinical experiments and clinical trials to confirm the influence of microorganisms in the interaction of antibiotics and ICIs.

Probiotics and immune checkpoint inhibitors

Currently, several clinical trials combining probiotics and ICIs are underway. It has been found that oral probiotics restore anti-cancer immunity and the efficacy of ICIs through a pleiotropic mechanism.

However, the changes in the tumor micro-environment caused by oral probiotics are still unclear, so it needs to be detected in future clinical trials.


Generally speaking, microorganisms, including bacteria, fungi, viruses and their components and metabolites, exist in various tumor tissues, forming a tumor microbe microenvironment. Current research has revealed the role of some microorganisms as immune activators, inhibitors or bystanders.

Taking into account the multi-faceted effects of the tumor micro-environment, its regulatory strategies including synthetic biology, antibiotics and probiotics can be used as a potential combination of immunotherapy.

The tumor microbe microenvironment is a new field facing major challenges and opportunities. A comprehensive understanding of tumor microbes and their role in tumor immune microenvironment will provide a conceptual shift in the study of tumor-immune-microbe relationships.

The tumor microbiome may be used as a prognostic or predictive tool, which may also help develop new anti-cancer drugs. Importantly, it may open the next wave of precision medicine and immunotherapy combined strategies.


1.The role of the tumor microbemicroenvironment in the tumor immune microenvironment: bystander, activator, orinhibitor? J Exp Clin Cancer Res. 2021; 40: 327.

How does the tumor micro-environment affect immunotherapy?

(source:internet, reference only)

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