Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance

作者：Linlin Shi, Jianyong Sheng, Guozhong Chen, Peng Zhu, Changping Shi, Bei Li, Chaiwoo Park, Jingyi Wang, Bixiang Zhang, Zhi Liu, Xiangliang Yang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2020 · DOI：10.1136/jitc-2020-000973 · 被引用次数：133 · 研究领域：Probiotics and Fermented Foods、Cancer Research and Treatments、Gut microbiota and health

Background Interleukin-2 (IL-2) serves as a pioneer of immunotherapeutic agent in cancer treatment. However, there is a considerable proportion of patients who cannot benefit from this therapy due to the limited clinical responses and dose-limiting toxicities. Mounting evidence indicates that commensal microbiota shapes the outcome of cancer immunotherapies. In this study, we aim to investigate the enhancing effect of Akkermansia muciniphila (AKK), a beneficial commensal microbe receiving considerable attentions, on the antitumor efficacy of IL-2 and explore the underlying molecular mechanism. Methods Colorectal carcinoma patient-derived tumor tissues were used to evaluate the therapeutic efficacy of combination treatment. AKK was orally delivered to B16F10 and CT26 tumor-bearing mice along with systemic IL-2 treatment. Flow cytometry was carried out to analyze the tumor immune microenvironment. The molecular mechanism of the enhanced therapeutic efficacy was explored by RNA-seq and then verified in tumor-bearing mice. Results Combined treatment with IL-2 and AKK showed a stronger antitumor efficacy in colorectal cancer patient-derived tumor tissues. Meanwhile, the therapeutic outcome of IL-2 was significantly potentiated by oral administration of AKK in subcutaneous melanoma and colorectal tumor-bearing mice, resulting from the strengthened antitumor immune surveillance. Mechanistically, the antitumor immune response elicited by AKK was partially mediated by Amuc, derived fr...