Exploring the Emerging Role of the Gut Microbiota and Tumor Microenvironment in Cancer Immunotherapy

Abstract

The tumor microenvironment (TME) is a complex ecosystem, which includes many different types of cells, abnormal vascular systems, and immunosuppressive cytokines. TME serves an important function in tumor tolerance and escapes from immune surveillance leading to tumor progression. Indeed, there is increasing evidence that gut microbiome is associated with cancer in a variety of ways, as specific microbial signatures are known to promote cancer development and influence safety, tolerability, and efficacy of therapies. Studies over the past five years have shown that the composition of the intestinal microbiota has a significant impact on the efficacy of anticancer immunosurveillance, which contribute to the therapeutic activity of cancer immunotherapies based on targeting cytotoxic T lymphocyte protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) axis. In this review, we mainly discuss the impact of TME on cancer and immunotherapy through immune-related mechanisms. We subsequently discuss the influence of gut microbiota and its metabolites on the host immune system and the formation of TME. In addition, this review also summarizes the latest research on the role of gut microbiota in cancer immunotherapy.

Keywords: gut microbiota; host immunity; immunotherapy; programmed cell death protein 1/programmed cell death 1 ligand 1; tumor microenvironment.

Figure 1

The role of TME in cancer and its immunotherapy. The main cells of the TME in cancer immunity are NK cells, DC cells, CD8 + T cells, Treg cells, fibroblasts, TAMs, and MDSCs. Among them, NK cells induce the death of tumor cells by the ways of releasing perforin and granzyme, secreting tumor necrosis factor-a, and mediating cytotoxicity by TRAIL and Fasl receptors. CDC1 cells are able to promote the differentiation and maturation of CD8⁺ T cells, and cDC1 cells can recruit CCL5 and XCL1, which induce the accumulation of cDC1 cells in the TME, thereby improving the immune control of tumors. IL-2 contributes to enhancing the antitumor activity of NK cells. When CD4 + T cells migrate to lymph nodes, cDC2 can activate CD4⁺ T cell responses. cDC2 resistant CD4 ⁺ T cells can be inhibited by Treg cells. VEGFA activates fibroblasts, which secrete FSP1. TAMs can promote the growth and metastasis of tumor cells through multiple pathways, lactate produced by cancer and acidification of the microenvironment increase ARG1 expression in TAMs. MDSCs affect the ability to respond to non-specific stimulation by producing ROS, etc., which leads to the inability of CD8⁺ T cells combined with pMHC.

Figure 2

Gut microbiota and its metabolites act on the host immune system to influence the shaping of the TME. TLR4 signaling in tumor cells is able to recruit neutrophils, while TNF released by neutrophils is able to induce metastasis of tumor cells. Gut microbiota is beneficial to reduce the number of neutrophils, which plays a promoting role in the treatment of tumors. Gut microbiota metabolite inosine significantly promotes the differentiation of Th1 cells in the presence of exogenous interferon-γ by acting on the A2A receptor on T cells, while SCFA can regulate the production of cytokines, affect the class conversion of B cells, activate DC cells and macrophages, and affect the differentiation of memory T cells, which also plays an important role in cancer therapy.

Figure 3

Role of gut microbiota in cancer immunotherapy. Gut microbes can stimulate the body to produce CD47 antibodies by activating STING signaling, thereby promoting immunotherapy. It is reported that the cross-priming of antigen-specific T cells of tumor-resident DCs can be enhanced by anti-CD47 therapy. In addition, type I IFN plays an important role in enhancing the adaptive immune response to anti-CD47 antibody therapy in tumor-resident DCs. Accumulation of Bifidobacteria in the TME can significantly improve the antitumor efficacy of anti-CD47 immunotherapy, which is dependent on STING signaling and type I IFN within DCs. Bifidobacteria may affect activating DC cells, thereby improving the activity of tumor-specific CD8⁺ T cells. The key role of B. fragilis is to restore the anti–CTLA-4 treatment response associated with Th1 immune responses in tumor-draining lymph nodes.