Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) proteins transformed the management of advanced cancers. Many tumor-intrinsic factors modulate immunological and clinical responses to such therapies, but ample evidence also implicates the gut microbiome in responses. The gut microbiome, comprising the bacteria, archaea, fungi, and viruses that live in the human digestive tract, is an established determinant of host immunity, but its impact on response to ICI therapy in mice and humans with cancer has only recently been appreciated. Therapeutic interventions to optimize microbiota composition to improve immunotherapy outcomes show promise in mice and humans with cancer. In this review, we discuss the rationale for gut microbiome–based cancer therapies, the results from early-phase clinical trials, and possible future developments.

Tumor antigen-specific cytotoxic T cells are present in advanced cancers but often fail to induce tumor rejection (1–3) because cancer cells utilize many tumor-intrinsic mechanisms to escape immune- mediated destruction. Among these, the programmed death 1/pro- grammed death ligand 1 (PD-1/PD-L1) axis is a key player in the inhibition of cytotoxic CD8þ T cells, and immune checkpoint inhi- bitors (ICI) targeting PD-L1 promote effective and often durable responses in patients with a variety of cancer types, including mela- noma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC; refs. 4–6). Biomarkers of response to PD-L1 blockade include CD8þ tumor-infiltrating lymphocytes (TIL; refs. 7, 8), IFNg gene expression (9, 10), high tumor mutation burden (TMB; refs. 10–12), or PD-L1 expression on tumor or T cells (5, 13). Strikingly, multiple studies support the role of the gut microbiome in regulating clinical responses to ICI in various preclinical models and in patients with cancer. In this review, we (i) summarize preclinical and clinical data supporting the role of the gut microbiome in determining response to cancer immunotherapy; (ii) describe the spectrum of therapeutic strategies to target the microbiome in cancer and their present status; and (iii) present key unanswered questions to address in ongoing and future research.

Potential mechanism(s) to explain the impact of gut microbiota on cancer immunotherapy

The precise mechanisms underlying how gut microbiota influence cancer immunotherapy are poorly understood, but research has converged upon three themes bacteria or bacterial components that directly stimulate antitumor T-cell responses, molecular mimicry between shared bacterial and tumoral epitopes, and bacterial metabolites that shape antitumor immunity.

Some gut bacteria can elicit defined antigen-specific T-cell responses, including Helicobacter spp. [RORgtþ FOXP3þ inducible T-regulatory cells (iTreg)] and A. muciniphila (IgG1 antibodies and Tfh cells. Others exert immunostimulatory properties either directly or after being sensed by DCs in gut-associated lymphoid tissue (GALT), spleen, and/or tumor draining lymph nodes. These include: B. thetaiotaomicron or B. fragilis, which enhance the efficacy of CTLA-4 treatment, and E. hirae and B. intestihominis, which directly enhance the intratumoral CD8/Treg ratio and IFNg-

producing gd T cells, respectively, following cyclophosphamide treat- ment. Others include B. rodentium, which stimulates antitumor responses in Rnf5/ ice in a My8DD/TLR-mediated fashion, and Bifidobacterium spp., which sensitizes mice to anti-CD47 immu- notherapy in a STING-and IFN-dependent fashion. Separately, bacterial flagellin directly interacts with TLR5; in cancer, bacterial flagellin derived from E. gallinarum and S. typhimurium demonstrate immunostimulatory potential.

Molecular mimicry between pathogens and tumor antigens can also elicit cross-reactive T cells via antigenic mimicry. Preclinically, both Bifidobacterium breve and the E. hirae bacteriophage elicited commensal-specific T cells that cross-reacted with candidate neoanti- gens. In humans, long-term survival in pancreatic cancer was associated with the development of highly immunogenic neoantigens with predicted cross-reactivity to microbial epitopes. Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models; this bacterium interacts with the inhibitory T-cell receptor TIGIT through FAP2 and can directly suppress antitumor immunity and inhibit tumor killing by natural killer (NK) cells. Collectively, these data suggest that certain commensals may influence adaptive and/or innate responses to cancer by modulating inhibitory checkpoint pathways. Finally, human

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