Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies

Abstract

Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

Keywords: cancer; gut microbiota; immune‐related adverse events; immunotherapy; precision medicine; predominant bacteria.

Figure 1

The role of gut microbiota in cancer immunotherapy. Through manipulation of commensals in cancer patients by diet interventions, fecal microbial transplant, prebiotics, probiotics and bacteria consortia, host antitumor immunity can be enhanced by dominance of “beneficial” bacteria in gut lumen and their metabolites. Increased effector T cells and induction of Tregs can be seen in GALT, which leads to improved clinical outcomes of cancer immunotherapy with lower incidence of immune‐related adverse events. FMT, fecal microbiota transplant; GALT, gut‐associated lymphoid tissue; GZMB, granzyme B; IFN‐γ, interferon‐γ; IL‐10, interleukin‐10; PFN, perforin; TNF‐α, tumor necrosis factor‐α; Treg, regulatory T cell.

Figure 2

Human microbiota disruption contributes to various diseases including cancers, bowel diseases, liver diseases, chronic kidney diseases, cardiovascular diseases, respiratory diseases, metabolic diseases, and neurologic and psychiatric diseases. IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IFN‐γ, interferon‐γ; IL‐10, interleukin‐10; IL‐12, interleukin‐12; LPS, lipopolysaccharides; NAFLD, nonalcoholic fatty liver disease; SCFAs, short‐chain fatty acids; TNF‐α, tumor necrosis factor‐α.

Figure 3

The mechanisms underlying the immunostimulatory involvement of gut microbiota in cancer immunotherapy. Anticancer therapies such as chemotherapy, radiotherapy and immunotherapy can increase permeability of gut epithelial, translocation of bacteria and dysbiosis. During cancer therapy, antibiotics are sometimes used to treat opportunistic infection, which can also lead to disruption of gut microbiota. The mechanism of immunostimulation by gut microbiota includes ligation of PRR and PAMP, release of microbial metabolites such as SCFAs, LPS and inosine, and cross‐reactivity of bacteria epitope‐specific T cells and tumor antigen‐specific T cells. LPS, Lipopolysaccharides; MDSC, myeloid‐derived suppressor cells; PAMP, pathogen‐associated molecular patterns; PRR, pattern recognition receptor; SCFAs, short‐chain fatty acids.

Figure 4

Influence of beneficial gut microbiota in diverse cancer types during immunotherapy. Gut microbiota has contrast role in cancer initiation and development, which not only affects gastrointestinal (GI) cancer locally, but also impacts cancer developed in distal organs including nonsmall‐cell lung cancer, hepatocellular carcinoma, hematologic malignancies, renal cell cancer, and melanoma.