Abstract

The clinical management of cancer patients compromises the delicate symbiosis between the gut microbiota and the host. Mucositis, a major oncological problem caused by anticancer chemotherapeutic agents, is worsened by neutropenia and antibiotics. Our group has reported the crucial role of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer. By compromising intestinal integrity, chemotherapeutic agents enhance gut permeability and favor the selective translocation of Gram⁺ bacteria (L. johnsonii + E. hirae) into secondary lymphoid organs. There, anti-commensal pathogenic TH17 (pTh17) T cell responses are primed, facilitating the intratumoral accumulation of tumour-specific TH1 T cells that is associated with tumour regression after chemotherapy with cyclophosphamide (CTX) (Viaud et al Science Nov 2013). To demonstrate a causal relationship between gut microbiota and systemic pTh17 responses induced by CTX, we treated animals that had been previously sterilised by means of antibiotics with a cocktail of Gram⁺ bacteria (L. johnsonii + E. hirae) and found that this cocktail (but not L. reuteri or L. plantarum) could induce pTh17 in the spleen of CTX (but not vehicle) -treated animals and restored the CTX- anti-cancer effects lost in antibiotic-treated mice (Daillère, unpublished data). Importantly, the redox equilibrium of myeloid cells contained in the tumour microenvironment is also influenced by the intestinal microflora, contributing to tumour responses (Iida, Science Nov 2013). Moreover, we just extended these findings to immune checkpoint blockade by anti-CTLA4 Ab and identified other microbial species responsible for the efficacy of the product in mice and potentially in humans (Vétizou, submitted). These data will be presented at the meeting. Hence, the anticancer efficacy of alkylating agents, platinum salts and immunomodulators could be compromised in patients presenting a dysbiosis or co-treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of conventional chemotherapeutics.