Abstract
Abstract Gut microbiota is now recognized as a key player impacting the host’s anti-cancer immunosurveillance and ability to respond to immunotherapy. Its optimal modulation for preventive and therapeutic purposes is very appealing. Since diet is one of the most powerful modulators of the microbiota, nutritional interventions could be leveraged to improve host immunity. The present study aims to analyze the anticancer properties of inulin, a fiber known to promote bacteria described as immunostimulatory. The effects of inulin complementation were tested in mice fed an inulin-enriched diet for 2 weeks before tumor implantation. In the three tumor models used (melanoma, fibrosarcoma, and colorectal cancer), inulin consumption inhibited tumor growth by 80% compared to controls. Tumor-infiltrated immunity analysis showed that inulin triggers an enhanced Th1-polarized CD4 +CD8 +and γδ T cell-mediated antitumor response. In the gut, inulin consumption favored Bifidobacterium relative abundance, and strengthened gut immunity, by increasing the proportion of colonic IFNγ-producing γδ intra-epithelial T lymphocytes as well as the expression of genes involved in inflammation. In addition, we showed that the inulin-mediated anti-tumor effect is gut microbiota- and γδ T cell-dependent, as both antibiotic treatment and in vivo blocking of γδ TcR abrogate inulin efficacy. Overall, our data identified γδ T cells as a critical immune subset, mandatory for inulin-mediated antitumor immunity in vivo. This supports and rationalizes the use of a prebiotic approache as well as the development of immunotherapies targeting γδ T cells in cancer prevention and treatment. This work is supported by GEFLUC Dauphiné-Savoie, Ligue contre le Cancer Comité Isère, Ligue contre le Cancer Comité Savoie, Université Grenoble Alpes IDEX Initiatives de Recherche Stratégiques. Emilie Boucher is supported by a grant salary from the French Ministry of Higher Education, Research and Innovation.
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