Cancer and the Microbiome-Influence of the Commensal Microbiota on Cancer, Immune Responses, and Immunotherapy

Abstract

The commensal microbiota has been implicated in the regulation of a diverse array of physiological processes, both within the gastrointestinal tract and at distant tissue sites. Cancer is no exception, and distinct aspects of the microbiota have been reported to have either pro- or anti-tumor effects. The functional role of the microbiota in regulating not only mucosal but also systemic immune responses has led to investigations into the impact on cancer immunotherapies, particularly with agents targeting the immunologic checkpoints PD-1 and CTLA-4. Microbial sequencing and reconstitution of germ-free mice have indicated both positive and negative regulatory bacteria likely exist, which either promote or interfere with immunotherapy efficacy. These collective findings have led to the development of clinical trials pursuing microbiome-based therapeutic interventions, with the hope of expanding immunotherapy efficacy. This review summarizes recent knowledge about the relationship between the host microbiota and cancer and anti-tumor immune response, with implications for cancer therapy.

Keywords: Anti–PD-1; Cancer Immunotherapy; Checkpoint Blockade Therapy; Gut Microbiome; Tumor Microbiome.

Figure 1.

Local effects of the gut microbiota on tumor development. Gastric cancer: H pylori release virulence factors (eg, CagA, VacA) causing endoplasmic reticulum (ER) stress, autophagy, and oxidative stress in gastric epithelial cells, which collectively contribute to cancer development. RNS, reactive nitrogen species; ROS, reactive oxygen species. Colorectal cancer: F nucleatum contributes to tumor development and progression via several mechanisms. The virulence factor FadA can signal through E-cadherin and lead to an increase in annexin A1 expression, activation Wnt/β-catenin signaling, and up-regulation oncogenes c-Myc and cyclin D1. Signaling through TLR4 activates of NF-κB and up-regulation of microRNA-21 (miRNA-21), which also has oncogene functions. Signaling through TLR4 also induces MyD88-driven autophagy in cancer cells, thus aiding in chemoresistance. The outer membrane protein Fap2 binds to inhibitory TIGIT receptor on tumor-infiltrating NK cells and T cells, thus aiding in cancer immune evasion. Other gut bacteria, such as B fragilis, Campylobacter, and Proteobacteria, have also been associated with the development of CRC. Liver cancer: Gut bacterial metabolites (eg, secondary BAs) and microbe-associated molecular patterns, e.g., LTA and LPS) enter the liver via the hepatic portal vein and exert diverse effects on various cells in the liver that collectively contribute to cancer development and immune evasion. LPS-driven TLR4 signaling up-regulates the hepatomitogen epiregulin in hepatic stellate cells (HSCs), which can contribute to cancer development. Enrichment of Clostridium can result in accumulation of LTA and of the secondary BA deoxycholine, which collectively signal via TLR2 and up-regulate COX2, causing increase in prostaglandin E₂ (PGE₂), which in turn inhibits tumor cell killing by infiltrating CD8⁺ T cells, thus contributing to cancer immune evasion. Secondary BAs can also inhibit secretion of CXCL16 by liver sinusoidal endothelial cells (LSECs) required for recruitment of NKT cells, thus further contributing to cancer immune evasion. Pancreatic cancer: Gut bacteria found in pancreatic tumors, such as Bacillus clausii, Sachharopolyspora, Streptomyces, and Pseudoxanthomonas, are associated with improved antitumor immunity in pancreatic cancer, and Gammaproteobacteria contribute to resistance to gemcitabine chemotherapy by metabolizing the active form of the drug. The route of translocation from the gut to the pancreas is likely via the pancreatic duct, which opens into the duodenum. MDSC, myeloid-derived suppressor cells.

Figure 2.

Systemic effects of the gut microbiota on antitumor immunity and immunotherapy. The gut microbiota could modulate immunotherapy outcomes by stimulating or inhibiting antitumor immunity. The messengers that could carry signals from the gut and/or gut-associated lymphoid tissues (GALT) to a distant tumor site include (1) bacterial metabolites that enter the circulation and regulate gene expression in various cells; (2) microbe-associated molecular patterns (MAMPs), which can modulate innate immunity by signaling through pattern recognition receptors, such as TLRs; (3) whole viable bacteria could potentially translocate and affect immune responses or drug activity in distant tumor tissues; (4) immune cells conditioned by sensing microbiota signals in the GALT could migrate and carry out immune-stimulatory or -inhibitory functions in distant tumors; and (5) cytokines could be released in the GALT in response to microbial stimuli and potentially enter the circulation and modulate downstream immune functions systemically. APC, antigen presenting cell; MDSC, myeloid-derived suppressor cell; MLN, mesenteric lymph node.