Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.

Identification of a N6-Methyladenosine (m6A)-Related lncRNA Signature for Predicting the Prognosis and Immune Landscape of Lung Squamous Cell Carcinoma

“…The immune microenvironment includes various immune cells and secreted factors ( 35 ). The infiltration of tumor cells, the immune functions, as well as the expression of immune checkpoint inhibitors could influence the prognosis of cancer patients as well as predict the response to immunotherapies ( 35 , 36 ). Manipulating the expression of m6A regulators or lncRNAs could modify the immune microenvironment and immune-related biological processes ( 15 , 29 ).…”

A Diversity Outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors

“…Cage grouping has a significant effect on microbiome composition and the lack of clustering of responders within cages suggests that differences in the microbiome did not influence outcomes in our study ( 51 ). The gut microbiome is an area of intense investigation for ICI response and may reveal predictive biomarkers and therapeutic strategies to improve ICI success rates including microbiota transplants ( 52 ). Future investigation using DOF1 or CCF1 mice could provide an opportunity to investigate microbiome influence on ICI, and yield insight into interactions between the genome, the microbiome, and anti-tumor immunity.…”

“…B16F0 specific Ab and T cell response. B16 reactive T cells were assayed by IFN-γ ELISPOT assay as previously described (52). ELISPOT plates were coated with anti-mouse IFN-γ antibody (clone AN18, Invitrogen) and incubated overnight at 4 °C.…”

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

“…The potential mechanisms through which the immune response is regulated by the microbiome may be as follows ( Mazmanian et al, 2005 ; Helmink et al, 2019 ; Hayase and Jenq, 2021 ): 1) Through linkage between PAMPs and pattern recognized receptors (PRRs, such as Toll-like receptors), the adaptive immune response can be activated by APCs. 2) Cancer cells can bear cross-reactive neoantigens with microbiota, thus inducing an immune response.…”