Recent evidence provides further insight into the therapeutic effects of CTLA-4 blockade, revealing that the immunostimulatory and antitumor effects of this ICB depend on distinct Bacteroides species of the gut microbiota [233]. CTLA-4 mAb lost its therapeutic efficacy against established melanomas, colon cancers, and sarcomas in mice that were reared under germ-free conditions or that had been raised in specific pathogen-free environment and then treated with multiple broad-spectrum antibiotics to sterilize the gut. This defect was overcome by gavage with Bacteroides fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells, suggesting a therapy-relevant cross-reactivity between microbial and tumor antigens recognized by the same TCR. Accordingly, both in mice and in patients, T cell responses specific for distinct Bacteroides species (B. fragilis and B. theraiotaomicron) were correlated with the administration and efficacy of CTLA-4 blockade. Furthermore, fecal microbial transplantation of feces harvested from each of these patient clusters into germ-free tumor-bearing mice highlighted that the microbial composition of cluster C, rich in immunogenic Bacteroides spp. (mainly contributing to the niching of B. fragilis), could restore anti-CTLA-4 mAb efficacy, whereas cluster B enriched with tolerogenic Bacteroides species mediated complete resistance to the mAb. A parallel study to that above has shown a role for distinct components of the gut microbiota, especially Bifidobacterium, in promoting natural antitumor immune responses [234]. Sivan et al. compared the antitumor CTL responses in genetically similar C57BL/6 tumor bearers derived from two different mouse facilities, the Jackson Laboratory (JAX) and Taconic Farms (TAC), to have differing commensal microbes. JAX and TAC mice exhibited significant differences in the growth kinetics of subcutaneously implanted melanomas; more aggressive tumors in TAC mice were attributable to lower tumor-specific T cell responses elicited in draining lymph nodes and poor intratumoral accumulation of tumor-antigen-specific CD8+ T cells. The aggressive neoplastic growth in TAC mice could be reduced to the rates seen in JAX mice after either JAX fecal transplantation or cohousing between the mice. Notably, Bifidobacterium was identified as associated with the enhanced tumor control. Hence, oral feeding of TAC mice with Bifidobacterium or cohousing of TAC and JAX mice restored CTL responses and allowed the host to control tumor progression by activating the processing and presentation machinery of intratumoral immune cells. More importantly, the microbiome also effects the therapeutic efficacy of PD-L1 blockade. Injection of a blocking antibody against PD-L1 was much more efficient in reducing the growth of melanomas in mice containing a high abundance of Bifidobacterium in their gut than in mice lacking this genus. Bifidobacterium-induced TIL enrichment of the TME also allowed for enhanced antitumor effects mediated by anti-PD-L1 mAb immunotherapy. DCs purified from mice that had been treated with Bifidobacterium were particularly active in presenting a melanoma-driven peptide antigen to T cells for stimulation of their proliferation and IFN-γ production, suggesting that Bifidobacterium improves the antitumor immune response by an effect on DCs. Hence, the mechanistic bases of the microbial contribution to the mode of action of distinct checkpoint blockers share common features but might also somewhat differ. While both studies describe the gut microbiota-dependent intratumoral maturation of DCs, the first study (on anti-CTLA4) suggests a role for cross-reactive T cell epitopes present on bacteria and cancer, the latter (on anti-PD-L1) postulates an effect on innate immunity leading to a gut microbiota-dependent resetting of antigen presenting cell functions. In addition to pre-clinical mouse models, two recent papers reveal that gut microbiome can also influence the efficacy of PD-1-based immunotherapy against epithelial tumors and melanoma in patients [235, 236]. In one article, Zitvogel and collaborators show that fecal microbiota transplantation from cancer patients who responded to ICB into germ-free or antibiotics-treated mice alleviates the antitumor effects of PD-1 blockade [235]. Notably, oral supplementation with Akkermansia muciniphila post-fecal microbiota transplantation with non-responder faces restored the efficacy of PD-1 blockade in an IL-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds. Whereas in another paper, Wargo and colleagues demonstrate that significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus non-responders, and analysis of patient fecal microbiome samples showed significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria in responding patients [236]. Tellingly, immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients.
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