National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-000973.
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 (AKK), a beneficial commensal microbe receiving considerable attentions, on the antitumor efficacy of IL-2 and explore the underlying molecular mechanism.
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.
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 from the outer membrane protein of AKK, through activating toll-like receptor 2 (TLR2) signaling pathway. Besides, oral supplementation with AKK protected gut barrier function and maintained mucosal homeostasis under systemic IL-2 treatment.
These findings propose that IL-2 combined with AKK is a novel therapeutic strategy with prospecting application for cancer treatment in clinical practice.
白细胞介素-2（IL-2）作为癌症治疗的免疫治疗药物先驱。然而，由于临床反应有限和剂量限制毒性，相当一部分患者无法从中受益。越来越多的证据表明，共生微生物群影响癌症免疫治疗的结果。在这项研究中，我们旨在研究有益共生微生物 Akkermansia muciniphila（AKK）对 IL-2 的抗肿瘤疗效的增强作用，并探讨其潜在的分子机制。
使用结直肠癌患者来源的肿瘤组织评估联合治疗的疗效。同时给予 AKK 口服和全身 IL-2 治疗 B16F10 和 CT26 荷瘤小鼠。采用流式细胞术分析肿瘤免疫微环境。通过 RNA-seq 探讨增强治疗效果的分子机制，并在荷瘤小鼠中进行验证。
IL-2 和 AKK 联合治疗在结直肠癌患者来源的肿瘤组织中表现出更强的抗肿瘤疗效。同时，AKK 的口服给药显著增强了皮下黑色素瘤和结直肠肿瘤荷瘤小鼠中 IL-2 的治疗效果，这是由于抗肿瘤免疫监测的增强。在机制上，AKK 诱导的抗肿瘤免疫反应部分是由 AKK 外膜蛋白衍生的 Amuc 通过激活 toll 样受体 2（TLR2）信号通路介导的。此外，口服补充 AKK 可在全身 IL-2 治疗下保护肠道屏障功能并维持黏膜稳态。
这些发现表明，IL-2 联合 AKK 是一种有前途的癌症治疗新策略，具有临床应用前景。
