Review how the tumor microenvironment affects immunotherapy?

Preface

The effect of tumor immunotherapy depends to a large extent on the tumor microenvironment, especially the tumor immune microenvironment

Tumor microbial microenvironment plays many roles in tumor immune microenvironment, and it can be used as immune activator, inhibitor or bystander

(1) There are microbial antigens in cancer cells and immune cells,

(2) Microbial antigens mimic tumor antigens,

(3) Microbes induce immunogenic cell death

(4) Microorganisms mediated by pattern recognition receptors

(5) Microbial-derived metabolites

(6) Suppress microbial stimulation at checkpoints

In general, the tumor microenvironment regulates the tumor immune microenvironment, making it a potential target for improving immunotherapy

Tumor microenvironment

The human body contains trillions of microorganisms, some of which contribute to carcinogenic or anti-cancer reactions

Some microbial metabolites, including fatty acids and inosine, can accumulate in tumors and bind to cancer cell and immune cell receptors

The microenvironment formed by them is different from the usually mentioned tumor microenvironment, so it can be used as a new type of tumor microbe microenvironment, called "tumor microbe microenvironment"

The tumor microenvironment has important clinical significance

Certain microorganisms specifically accumulate in tumor tissues, and the fact that microorganisms are attracted to tumors makes these microorganisms used as precise anti-cancer drug carriers

In pancreatic cancer, the tumor microbiome of long-term surviving patients has higher alpha diversity and Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Klaus Bacillus characteristics than patients with shorter life spans

The Mechanism of Action of Tumor Microbial Microenvironment

Many studies have observed the correlation between tumor microbes and tumor microenvironment

(1) There are bacterial peptides in cancer cells and immune cells,

(2) Bacterial antigens mimic tumor antigens

(3) Microbes induce immunogenic cell death

(4) Auxiliary pattern recognition receptor-mediated signaling pathway

(5) Metabolites derived from microorganisms

(6) Stimulus inhibition checkpoint

Microbial antigens can activate anti-tumor T cells

Two key steps are required to successfully induce an adaptive anti-tumor response

Bacterial peptides are ubiquitous in melanoma metastasis

However, there are still some problems with bacterial peptides as tumor-specific antigens

Microbial antigen mimics the activation of anti-tumor T cells

Antigenic mimicry means that microbial antigens and tumor antigens have similar epitopes

Alexandra Snyder and colleagues analyzed tumor neoantigen epitopes in melanoma patients with different prognosis
.
They found that some tumor neoantigen epitopes have homology with microbial epitopes, and the higher the homology, the better the clinical prognosis
.
This finding indicates that similar antigens are present in tumors and may affect the immune response
.

Shin Heng Chiou and his colleagues analyzed the sequences of 770,000 T cell receptors in 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 a variety of lung cancer samples
.
In the future, it is necessary to explore mimics of microbial antigens present in various types of tumors
.
These "mimicking antigens" may provide new prospects for cancer treatment
.

Microbes induce 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 caused by microorganisms
.
Some researchers have combined an empty bacterial envelope with oxaliplatin to treat a mouse model of advanced colorectal cancer
.
This combined strategy strengthens ICD, strongly inhibits tumor growth and prolongs the survival time of mice
.

Oncolytic viruses or bacteria specifically target the tumor microenvironment, dissolve tumor cells, release tumor antigens, damage-related molecular patterns, and pathogen-related molecular patterns, recruit surrounding 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 effect of pathogen-related molecular patterns from microorganisms
.
Pathogen-related molecular patterns can be sensed by pattern recognition receptors (PRR)
.
Toll-like receptor (TLR) is currently the most studied subtype of PRR
.
The microbial activation of TLR plays a double-edged sword role in the tumor immune microenvironment
.

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

On the other hand, the microorganisms in the tumor maintain the immune-stimulated tumor microenvironment through tlr and play an anti-cancer effect
.
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
.

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

Microbial Metabolite Derivation

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
.

Short-chain fatty acids are the products of dietary fiber fermented by intestinal anaerobic bacteria
.
Short-chain fatty acids include 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 primary 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-polyphenolic acid, down-regulate the secretion of sinusoidal endothelial cell chemokine CXCL16
.

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

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 inhibition checkpoint

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

Helicobacter pylori acts on CEACAM1 through the CEACAM1 outer membrane protein HopQ to suppress immune cells
.
In addition to Helicobacter pylori and Fusobacterium nucleus, 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 can eliminate bifidobacteria and reduce CD47 blocking effect, suggesting that bifidobacteria may be a potential adjuvant for CD47 blocking
.

Clinical Application of Tumor Microbial Microenvironment

Three elements are required 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) in the treatment of non-muscle invasive bladder cancer and the use of the oncolytic virus talimogenelaherparepvec (T-VEC) in the treatment of advanced melanoma are two successful examples of tumor micro-environment regulation
.

Synthetic biology

Microbes have long been used as programmable drug delivery platforms
.
Recently, microorganisms have been designed to enhance immunotherapy
.
In this study, a non-pathogenic E.
coli strain loaded with CD47 nanobody blocker was designed
.
This strain colonizes the tumor, releases the CD47 nanobody inhibitor, and then activates tumor-infiltrating T cells to eliminate the tumor
.

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

For example, the Fusobacterium nuclei specific phage and nanosilver complex can clear the Fusobacterium nucleus in tumors, reduce myeloid-derived suppressor cells in tumors, and enhance the efficacy of ICIs
.

Antibiotics and immune checkpoint inhibitors

Clinically, the use of antibacterial drugs is negatively correlated with the clinical efficacy 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 affect the efficacy of ICIs;

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

Probiotics and immune checkpoint inhibitors

Currently, some clinical trials combining probiotics and ICIs are underway
.
Studies have found that oral probiotics can restore the anti-cancer immunity and efficacy of ICIs through a multi-effect mechanism
.

However, the impact of oral probiotics on the tumor microenvironment is unclear and needs to be tested in future clinical trials
.

Summarize

Generally speaking, microorganisms, including bacteria, fungi, viruses and their components and metabolites, exist in various tumor tissues to form a tumor micro-environment
.
Current research reveals the role of some microorganisms as immune activators, inhibitors or bystanders
.

Taking into account the many aspects of the tumor microenvironment, its regulatory strategies include synthetic biology, antibiotics and probiotics, which can be used as a potential immunotherapy combination
.

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

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

 (Source: Internet, reference only)