Critical role of the gut microbiota in immune responses and cancer immunotherapy

Abstract

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

Keywords: Cancer immunotherapy; Gut microbiota-derived metabolites; Immune checkpoint inhibitors; Immune-related adverse events; Microbiota modification.

Fig. 1

The interplay between the immune system and the gut microbiota in non-GI tract lymphoid organs. The gut microbiota and its metabolites influence the development of host bone marrow and thymus. For instance, SCFAs are capable of facilitating hematopoiesis recovery of bone marrow after radiation damage.The gut microbiota also induce the translocation of selected bacteria into and stimulate immunocytes and immune responses of the spleen after CTX treatment

Fig. 2

The interplay between the innate immune system and the gut microbiota in GI tract. Some mechanisms utilized by the gut microbiota to interact with the host innate immune system in GI tract are described above. The interplay between the gut and its microbiota is complex. The secretion of AMPs could be affected by A.muciniphila. PRRs are strongly affected by the presence of the gut microbiota. Microbiota-derived TLR and NOD ligands act directly on intestinal immunocytes and can activate inflammatory genes. Bacteroides fragilis stimulates the downstream PI3K pathway and activates the transcription of anti-inflammatory genes by co-operating TLR1/TLR2 heterodimer and Dectin-1. NLRs function to activate inflammatory caspases and cytokines to compost optimal microbiota and maintain intestinal homeostasis. Microbial metabolites taurine, histamine, and spermine have been identified to regulate the activation of NLRP6 inflammasome as well as the induction of downstream epithelial IL-18 and AMPs secretion. Innate immune cells, including macrophages, DCs, and NK cells, interact heavily with the gut microbiota. OMVs derived from Bacteroides elicit IL-10 production by DCs, as well as enhance the phagocytic functions of macrophages triggered by the bacteria themselves. The expression of the transcription factor RORγt and IL-22 of intestinal NK cells is conditioned by the commensal microbiota

Fig. 3

The interplay between the adaptive immune system and the gut microbiota in GI tract. Some mechanisms utilized by the gut microbiota to interact with the host innate immune system in GI tract are described above. Foxp3 + Treg cells promote maturation of B cells and production of secretary IgA. These contribute to the regulation of homeostatic microbiota composition and the maintenance of a non-inflammatory host-microbial relationship. CD8 + T cells can be activated by the intestinal microbiota and its metabolites. Butyrate, for instance, showed a direct antagonistic influence on the HDAC of CTLs and Tc17 cells, thereby promoting the expression of IFN-γ and granzyme B. As for Th cells, the adhesion of SFB to IECs is a common outcome of inducing homeostatic intestinal Th17 cells. Tfh cells, being another modulation target of gut microbiota modification, are essential for the production of plasma cells and memory B cells. The SCFAs have been demonstrated to regulate the size and function of the Treg cell pool

Fig. 4

Selected mechanisms of how the gut microbiota impact cancer immunotherapies. Current studies have revealed the close link between the gut microbiota and the efficacy of cancer immunotherapy. Grouped by immunotherapies and metabolites, outlined here are some selected mechanisms utilized by the gut microbiota and its metabolites to regulate immunocyte activation, cytokine secretion, metabolism restriction and tumor cell proliferation inside the TME to influence cancer immunotherapy effects

Fig. 5

Future intervention strategies to modificate gut microbiota in cancer immunotherapy. Targeting the association between the gut microbiome and cancer immunotherapy, modifying the gut microbiota with the latest intervention technologies could significantly advance the quality of individualized treatment. Listed here are the potential mechanisms behind the five microbiota modification strategies, which could be used to promote the efficacy of cancer immunotherapy in a precise manner. These intervention strategies are developed mainly based on current views of the crosstalk between the gut microbiota and the immune system. FMT, dietary regulation, probiotics, prebiotics, and engineered microbial products all can alter intestinal bacteria to enhance anti-tumor immune responses inside the TME, which consequently improve the efficacy of cancer immunotherapy