The Negative Impact of Antibiotics on Outcomes in Cancer Patients Treated With Immunotherapy

A New Independent Prognostic Factor?

A. Elkrief; L. Derosa; G. Kroemer; L. Zitvogel; B. Routy

Disclosures

Ann Oncol. 2019;30(10):1572-1579. 

In This Article

ATB-related Dysbiosis and Impact of ATB on Anticancer Therapy: Pre-clinical Data

In the past 3 years, transplantable mouse models of colon cancer (MC-38), fibrosarcoma (MCA-205), NSCLC (LLC), melanoma (RET) and RCC (RENCA) revealed that the presence of intestinal Bacteroides fragilis and Bifidobacterium were important for efficient tumor growth reduction by CTLA-4 and PD-1 blockade, respectively.[12,13] A preclinical experiment using daily ciprofloxacin injections during gemcitabine treatment induced reversal of gemcitabine resistance, thus further illustrating the role of the gut microbiome on different modalities of anticancer therapy.[36] Contributing to the hypothesis that the gut microbiota affects the systemic innate immune system, the oral administration of vancomycin, imipenem and neomycin pre-tumor inoculation in MC-38 (colon) and E4 (lymphoma) models reduced the absolute numbers of monocytes and neutrophils in the tumor microenvironment after treatment with anti-IL-10 or oxaliplatin.[37] Similarly, in the MCA-205 fibrosarcoma model, ATB treatment decreased the cyclophosphamide-induced antitumor immune response, correlating with the loss of Enterococcus hirae-elicited CD4+ T helper cells and an improvement of CD8+ to Treg cell ratio in the tumor immune infiltrate.[38,39] In contrast, the ATB metronidazole slows down the growth of patient-derived colon cancers inoculated into immunodeficient mice if such tumors contain Fusobacterium spp., suggesting that such bacteria play a pro-tumorigenic role.[40]

Further confirming the integral role that the gut microbiota plays on ICI efficacy, fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into ATB-treated mice restored the efficacy of PD-1 therapy.[10] In contrast, FMT from non-responder patients into ATB-treated mice failed to stimulate the PD-1 response. However, oral gavage with Akkermansia muciniphila, a commensal that consistently correlated with favorable prognosis in NSCLC and RCC patients under immunotherapy, conferred responsiveness to PD-1 therapy after FMT with non-responder feces in this setting.[10] Thus, specific bacterial species are endowed with the capacity to improve the efficacy of anticancer immune response.

In parallel, a Japanese group carried out FMT from healthy volunteers in GF mice and isolated a cluster of 11 gut bacteria inducing IFNγ-CD8+ T-cell production in the colon. These bacteria boosted CD103+ DC with high expression of MHC class I, which correlated with enhanced therapeutic efficacy of anti-PD-1.[41]

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