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Flora-ishing guts assist cancer immunotherapies

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Science Immunology  02 Feb 2018:
Vol. 3, Issue 20, eaat0813
DOI: 10.1126/sciimmunol.aat0813

Abstract

Gut bacteria influence patient response to cancer therapy.

Immune checkpoint inhibitor therapies (ICIT) have been effective in promoting anti-tumor T cell responses to melanoma, non-small cell lung cancer, and renal cell carcinoma, resulting in improved survival rates. However, effective response rates are highly variable and seen in fewer than 50% of treated patients overall. ICIT include monoclonal antibodies (mAb) to cyotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein ligand-1 (PD-L1), and programmed cell death protein 1 (PD-1). Work in murine tumor models has suggested that the gut flora influences the effectiveness of ICIT. Now, Routy et al. report that disease-related or antibiotic-induced disturbances in the gut microbiome correlate with poor clinical responses to PD-1 blockade. Overall survival and anti-tumor responses of ICIT were significantly diminished by antibiotic treatment or in pathogen free tumor-bearing mouse models. Cancer patients treated for infection with antibiotics around the time of their first treatment with PD-1 or PDL-1 mAb had shorter progression-free survival (PFS) and overall survival (OS) as compared with controls. Further analysis revealed that antibiotic treatment was a predictor of primary resistance to ICIT independent of other prognostic markers for lung and renal cancer patients. These findings were replicated in a validation cohort. Other therapies that affect the gut microbiome, such as proton pump inhibitors, did not influence patient PFS or OS. To further explore the impact of gut dysbiosis on ICIT, they analyzed quantitative metagenomics of gut bacterial species from serial fecal samples of patients before and after PD-1 blockade. Favorable PFS and OS to ICIT correlated with the presence of Akkermansia muciniphila. CD4+ and CD8+ T cell interferon-γ secretion in recall responses to A. muciniphila correlated with PFS. Fecal microbiota transplantation (FMT) from ICIT responder patients into pathogen-free or antibiotic-treated mice conferred sensitivity to PD-1 blockade, in contrast to FMT from ICIT nonresponders. Oral gavage with A. muciniphila restored ICIT responses in tumor-bearing mice after FMT from nonresponders. Tumor growth delay was correlated with the presence of CCR9+ CXCR3+ CD4+ T cells and interleukin-12 production in the tumor microenvironment. Thus, these studies support a role for dysbiosis in primary resistance to ICIT and the potential for improved responses to these therapies.

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