Commensal Microbiota and Cancer Immunotherapy: Harnessing Commensal Bacteria for Cancer Therapy

Abstract

Cancer is one of the leading causes of death worldwide and the number of cancer patients is expected to continuously increase in the future. Traditional cancer therapies focus on inhibiting cancer growth while largely ignoring the contribution of the immune system in eliminating cancer cells. Recently, better understanding of immunological mechanisms pertaining to cancer progress has led to development of several immunotherapies, which revolutionized cancer treatment. Nonetheless, only a small proportion of cancer patients respond to immunotherapy and maintain a durable response. Among multiple factors contributing to the variability of immunotherapy response rates, commensal microbiota inhabiting patients have been identified as one of the most critical factors determining the success of immunotherapy. The functional diversity of microbiota differentially affects the host immune system and controls the efficacy of immunotherapy in individual cancer patients. Moreover, clinical studies have demonstrated that changing the gut microbiota composition by fecal microbiota transplantation in patients who failed a previous immunotherapy converts them to responders of the same therapy. Consequently, both academic and industrial researchers are putting extensive efforts to identify and develop specific bacteria or bacteria mixtures for cancer immunotherapy. In this review, we will summarize the immunological roles of commensal microbiota in cancer treatment and give specific examples of bacteria that show anticancer effect when administered as a monotherapy or as an adjuvant agent for immunotherapy. We will also list ongoing clinical trials testing the anticancer effect of commensal bacteria.

Keywords: Cancer; Fecal microbiota transplant; Immune checkpoint inhibitors; Immunity, mucosal; Immunotherapy; Microbiota.

Figure 1. The development of anticancer therapy.

(A) Major breakthroughs in anticancer therapy are depicted. (B) Compared to conventional anticancer therapies, immune checkpoint inhibitors are able to cure cancers in a subset of patients. Still, additional strategies need to be developed to increase the response rate of immune checkpoint inhibitors.

Figure 2. Regulation of intestinal immune cells by commensal bacteria.

(A) PSA released by B. fragilis makes dendritic cells to secrete TGF-β and induces Treg cell differentiation. Clostirdium spp. and Helicobacter spp. increase Treg cells by upregulating TGF-β and IDO. SFB increase production of IL-22 and SAA and promote dendritic cell-mediated Th17 cell differentiation. A. muciniphila induces differentiation of Tfh cells whereas Klebsiella spp. enhance Th1 cell differentiation. The mixture of 11 specific bacteria increases IFN-γ⁺CD8⁺ T cells in the intestine. (B) SCFA produced by bacteria-mediated fermentation of fibers promote Treg differentiation by activation of GPR43 and inhibition of HDAC. ATP generated by commensal bacteria induces Th17 cell differentiation. Intestinal bacteria metabolize bile acids to produce secondary bile acids. isoalloLCA increases Treg cells while 3-oxoLCA inhibits Th17 cell differentiation. Some commensal bacteria produce inosine which promotes differentiation of Th1 cells and increases IFN-γ⁺CD8⁺ T cells. Parts of figures were created with BioRender.com.

Figure 3. Experimental strategies for establishing causal relationship between commensal microbiota and efficacy of cancer therapeutics.

(A) Chemotherapy is effective in controlling tumor growth in mice raised in SPF conditions but not in germ-free or antibiotics (Abx)-treated mice which lack commensal bacteria. (B) Mice carrying human microbiota can be generated by transplanting feces from immunotherapy responders (N) or non-responders (NR) to germ-free mice. The immunotherapy is effective in mice having microbiota of the responders but not in mice having the non-responder’s microbiota.

Figure 4. The immune modulation by commensal bacteria in the context of anticancer therapy.

Regulation of various immune cell types by specific bacteria species in the context of immunotherapy or chemotherapy is depicted. Parts of figures were created with BioRender.com. DC: dendritic cell, GrB, granzyme B; MDSC, myeloid-derived suppressor cell; pTh17, pathogenic Th17; TAM, tumor-associated macrophage.