Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Pharmacology and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Sci Adv. 2021 Feb 17;7(8). doi: 10.1126/sciadv.abb6596. Print 2021 Feb.
Cancer fibrosis serves as a major therapeutic barrier in desmoplastic tumors. Relaxin (RLN; a systemic hormone) is efficacious to decrease fibrosis, but the in vivo mechanism of action is not clear. Considering the localization of relaxin family peptide receptor type 1 (RXFP1), the receptor for RLN, on macrophages, we hypothesize that macrophages can be modulated by RLN to ameliorate cancer fibrosis. Using KPC mouse model of pancreatic ductal adenocarcinoma (PDAC), here, we report locally expressed RLN with targeted gene delivery induces increased F4/80CD206 macrophages originating from Ly6C monocytes, promoting fibrosis depletion and cytotoxic T cell infiltration. Moreover, RLN gene delivery synergizes with PD-L1 blockade for tumor inhibition by enhancing T cell-mediated tumor cell killing and macrophage phagocytosis. Collectively, our results reveal previously unidentified insights into the modulation of macrophages to regulate tumor-associated fibrosis, providing a feasible strategy to reverse the immunosuppressive environment and improve the therapeutic outcome of checkpoint immunotherapies.
癌症纤维化是促结缔组织增生性肿瘤的主要治疗障碍。松弛素 (RLN；一种系统性激素) 可有效减少纤维化，但体内作用机制尚不清楚。鉴于松弛素家族肽受体 1 (RXFP1)，即 RLN 的受体，在巨噬细胞上的定位，我们假设 RLN 可以调节巨噬细胞以改善癌症纤维化。在这里，我们使用 KPC 小鼠胰腺导管腺癌 (PDAC) 模型报告了局部表达的 RLN 通过靶向基因传递诱导源自 Ly6C 单核细胞的 F4/80CD206 巨噬细胞增加，促进纤维化耗竭和细胞毒性 T 细胞浸润。此外，RLN 基因传递与 PD-L1 阻断协同作用，通过增强 T 细胞介导的肿瘤细胞杀伤和巨噬细胞吞噬作用抑制肿瘤。总之，我们的研究结果揭示了调节巨噬细胞以调节肿瘤相关纤维化的新见解，为逆转免疫抑制环境和改善检查点免疫疗法的治疗效果提供了可行的策略。
