The Effect of the Gut Microbiota on Systemic and Anti-Tumor Immunity and Response to Systemic Therapy against Cancer

Abstract

Gut microbiota can have opposing functions from pro-tumorigenic to anti-tumorigenic effects. Increasing preclinical and clinical evidence suggests that the intestinal microbiota affects cancer patients' response to immune checkpoint inhibitors (ICIs) immunotherapy, such as anti-programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Microbiota-induced inflammation possibly contributes to tumor growth and cancer development. Microbiota-derived metabolites can also be converted to carcinogenic agents related to genetic mutations and DNA damage in organs such as the colon. However, other attributes of microbiota, such as greater diversity and specific bacterial species and their metabolites, are linked to better clinical outcomes and potentially improved anti-tumor immunity. In addition, the intratumoral microbial composition strongly affects T-cell-mediated cytotoxicity and anti-tumor immune surveillance, adding more complexity to the cancer-microbiome-immune axis. Despite the emerging clinical evidence for the activity of the gut microbiota in immuno-oncology, the fundamental mechanisms of such activity are not well understood. This review provides an overview of underlying mechanisms by which the gut microbiota and its metabolites enhance or suppress anti-tumor immune responses. Understanding such mechanisms allows for better design of microbiome-specific treatment strategies to improve the clinical outcome in cancer patients undergoing systemic therapy.

Keywords: cancer; immune checkpoint inhibitors; immunotherapy; microbiota.

Figure 1

The interaction between gut microbiota and the immune system. The intestinal microbiota and their metabolites, including SCFAs, induce T-cell differentiation mainly on Tregs, Th1, and Th17 cells, impacting systemic immunity. The gut microbiota orchestrates Th1 differentiation from CD4⁺ T-cell by induction of STAT-3 and mTOR pathway. In addition, microbiota induces Treg development by the production of IL-10 and TGF-β. Microbiota and their metabolites may increase the Th17/Treg balance. The intestinal microbiota could activate CD8⁺ T-cells and NK cells which are critical in anti-tumor immunity. On the other hand, the immune system modulates systemic microbial translocation and inflammation through the activation of PRR signaling pathways as well as the production of AMPs. IEL: intraepithelial lymphocytes; PRR: pattern recognition receptor; AMP: antimicrobial peptides; DC: dendritic cell; NK: natural killer cell; ILC3: Type 3 innate lymphoid cells; TIGIT: T-cell immunoglobulin and ITIM domain.

Figure 2

The cancer—microbiota—immune system axis. The gut microbiota plays a critical role in the immune maturation and prevention of cancer development. The increase in commensal microbiota results in the enhancement of the immune system. While the reduction of beneficial bacteria is linked to tumor progression. Healthy microbiota composition potentially increases the accumulation and function of neutrophils, NK cells, CD4⁺, and CD8⁺ T-cells. On the other hand, using antibiotics may lead to dysbiosis, which can negatively affect T-cell function. The perturbation of gut microbiota consequently results in tumor growth and cancer development.

Figure 3

The influence of gut microbiota on the response to immune checkpoint inhibitors in cancer immunotherapy. Some microbes, including anaerobic commensal bacteria, which increase following sufficient dietary fiber intake, are associated with beneficial outcomes to checkpoint blockade immunotherapies such as anti-PD-1/PD-L1 and anti-CTLA4 antibodies [79]. Fecal microbiota transplantation could potentially improve the response in patients who failed to respond to such therapies.