Gut microbiome modulates efficacy of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.

Keywords: CTLA-4; Gut microbiome; ICIs resistance; Immunotherapy; PD-1/PD-L1.

Fig. 1

The potential mechanism of gut microbiome regulating ICIs efficacy. Firstly, the abundance of CTLA-4 on Tregs is upregulated by some bacteria and metabolites at baseline, which increases sensitivity to CTLA-4 blockade. Secondly, gut microbiota enhances the function of DCs. For example, Bifidobacterium promotes DCs maturation and decreases activation threshold, elevates recruitment and function of T cells by interaction with DCs. Thirdly, administration of Akkermansia muciniphila and Enterococcus hirae results in elevated CD4⁺ TCM in tumor bed. Fourthly, commensal bacteria are sensed by APCs, inducing pTh17 and Th1 differentiation, which influence tumor immunity by lymphocyte homing and recirculation. Fifthly, SCFAs are utilized by immune cells and gut epithelial cells as source of energy. Lastly, molecule mimicry theory and adjuvant effect participate in immune response