Intestinal microbes contribute to the efficacy of PD-L1 and CTLA-4 blockade.
Major finding: Intestinal microbes contribute to the efficacy of PD-L1 and CTLA-4 blockade.
Mechanism: Specific anticancer microbiota increase DC function, TH1 responses, and CD8+ T-cell accumulation.
Impact: Manipulation of the intestinal microbiome has the potential to improve the efficacy of immunotherapy.
Cancer immunotherapies including antibody-mediated programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade have had recent clinical success. The intestinal microbiota are an important mediator of systemic immune responses; however, their role in the response to cancer immunotherapy remains unclear. To address this question, Sivan, Corrales, and colleagues compared tumor growth in C57BL/6 mice from Jackson Laboratory (JAX) and Taconic Farms (TAC), which have different commensal microbes. Melanoma xenografts grew more slowly in JAX mice, which had increased tumor-specific T-cell responses and accumulation of intratumoral CD8+ T cells. Cohousing eliminated this difference in tumor growth, suggesting that commensal microbes might be responsible for the effect. Prophylactic fecal transfer from JAX mice to TAC mice delayed tumor growth and increased CD8+ T-cell infiltration. Comparative analysis revealed Bifidobacterium as the only taxa significantly increased in JAX mice compared with TAC mice that was positively correlated with antitumor T-cell responses. Treating TAC mice with Bifidobacterium reduced tumor growth, increased CD8+ T-cell accumulation, and improved the response to PD-L1 blockade. This effect was dependent on enhanced dendritic cell (DC) activation, resulting in augmented CD8+ T-cell–mediated antitumor immunity. In a related study, Vétizou and colleagues demonstrated that anti–CTLA-4 immunotherapy is more effective in controlling tumor progression in mice housed in a specific pathogen-free environment compared with a germ-free environment. Broad-spectrum antibiotics also reduced the efficacy of anti–CTLA-4 treatment, further highlighting the importance of gut microbiota in immunotherapy responses. Recolonization with specific Bacteroides species induced a TH1 phenotype and DC maturation and restored the response to anti–CTLA-4 in mice. In fecal transplants from patients with metastatic melanoma to mice, CTLA-4 blockade promoted Bacteroides fragilis outgrowth, which was associated with improved antitumor response. Together, these results highlight the importance of gut microbiota in cancer immunotherapy and suggest that manipulation of these microbes may improve antitumor responses.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
- ©2016 American Association for Cancer Research.