Modulation of gut microbiota: a novel approach to enhancing the effects of immune checkpoint inhibitors

Abstract

Although immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of some cancer patients, the majority still fail to respond adequately, and the available biomarkers cannot reliably predict drug efficacy. The gut microbiota has received widespread attention among the various intrinsic and extrinsic factors contributing to drug resistance. As an essential regulator of physiological function, the impact of gut microbiota on host immunity and response to cancer therapy is increasingly recognized. Several studies have demonstrated significant differences in gut microbiota between responders and nonresponders. The gut microbiota associated with better clinical outcomes is called 'favorable gut microbiota'. Significantly, interventions can alter the gut microbiota. By shifting the gut microbiota to the 'favorable' one through various modifications, preclinical and clinical studies have yielded more pronounced responses and better clinical outcomes when combined with ICIs treatment, providing novel approaches to improve the efficacy of cancer immunotherapy. These findings may be attributed to the effects of gut microbiota and its metabolites on the immune microenvironment and the systemic immune system, but the underlying mechanisms remain to be discovered. In this review, we summarize the clinical evidence that the gut microbiota is strongly associated with the outcomes of ICI treatment and describe the gut microbiota characteristics associated with better clinical outcomes. We then expand on the current prevalent modalities of gut microbiota regulation, provide a comprehensive overview of preclinical and clinical research advances in improving the therapeutic efficacy and prognosis of ICIs by modulating gut microbiota, and suggest fundamental questions we need to address and potential directions for future research expansion.

Keywords: cancer; fecal microbiota transplantation; gut microbiota; immune checkpoint inhibitors; probiotics.

Figure 1.

Gut microbiota modulates the antitumor immunity by several potential mechanisms in immunotherapy. (a) Microbial proteins cause T-cell cross-reactivity by mimicking tumor antigens. (b) Gut microbiota creates a relatively “hot” tumor microenvironment by regulating the expression and distribution of immune checkpoint molecules. (c) Microbes or microbial products activate PRRs, promoting tumor cell death by directly inducing or indirectly activating adaptive immune cells via cytokines released from surrounding cells or recruitment and activation of antigen-presenting cells to prime effector T cells. (d) Gut microbiome-derived SCFAs increase specific metabolites in the blood circulation of mice, particularly α-ketoglutaric acid, N-acetyl-l-glutamic acid, and pyridoxine, promoting the infiltration and activation of cytotoxic T lymphocytes and inhibiting the function of Tregs. (e) The intratumoral microbiome could be modulated by the intestinal microbiome, which might translocate to, colonize, and persist within tumors. Their peptides can be presented by the HLA-I and HLA-II molecules of melanoma cells and elicit T-cell cross-reactivity. Intratumoral Lactobacillus reuteri promotes antitumor T-cytotoxic 1 immunity via its metabolites, I3A, which acts through CD8⁺ T-cell-specific AhR signaling to promote IFN-γ and Gzm-B production in a CREB-dependent manner. (f) Inflammatory pathways can be detected in most of the pathways of immunotherapy regulated by gut microbiota, especially the T-cell receptor signaling pathway. Source: Created with BioRender.com. AhR, aryl hydrocarbon receptor; CREB, cAMP response element-binding protein; HLA-I and HLA-II, human leukocyte antigen class I and class II; I3A, indole-3-aldehyde; IFN-γ, interferon-γ; PRR, pattern recognition receptor; SCFA, short-chain fatty acids; Gzm-B, Granzyme B.