MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression.
MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression.
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MerTK介导的胞吞作用通过增强M2极化和PD-L1表达促进骨肉瘤的免疫耐受和肿瘤进展
DOI：
10.1080/2162402x.2021.2024941
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发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
Tao H
中科院分区：
文献类型：
--
作者：
Lin J;Xu A;Jin J;Zhang M;Lou J;Qian C;Zhu J;Wang Y;Yang Z;Li X;Yu W;Liu B;Tao H
摘要 骨肉瘤患者的免疫治疗进展缓慢，需要更深入地描述骨肉瘤微环境中的免疫耐受机制和新的治疗策略。吞噬细胞清除凋亡细胞，这一过程被称为“胞吞作用”，在肿瘤中普遍存在，并介导先天免疫炎症反应的抑制。考虑到骨肉瘤中存在大量浸润的巨噬细胞，胞吞作用可能是一个潜在的靶点，但在骨肉瘤中的研究很少。在这里，我们验证了胞吞作用后巨噬细胞的 M2 极化和 PD-L1 表达。使用药理抑制和基因敲低来探索潜在的途径。此外，在骨肉瘤模型中抑制胞吞作用后评估了肿瘤进展和免疫景观。我们的研究表明，胞吞作用促进了巨噬细胞的 PD-L1 表达和 M2 极化。骨肉瘤中的吞噬作用由 MerTK 受体介导，并通过 p38/STAT3 途径调节巨噬细胞的表型。通过建立小鼠骨肉瘤模型，我们强调抑制MerTK可以抑制肿瘤生长，并通过增加CD8+ T细胞的浸润和减少其耗竭来增强T细胞的细胞毒功能。我们的研究结果表明，MerTK 介导的胞吞作用通过增强巨噬细胞的 M2 极化和 PD-L1 诱导的免疫耐受（通过 p38/STAT3 通路调节）来促进骨肉瘤进展。
ABSTRACT The poor progress of immunotherapy on osteosarcoma patients requires deeper delineation of immune tolerance mechanisms in the osteosarcoma microenvironment and a new therapeutic strategy. Clearance of apoptotic cells by phagocytes, a process termed “efferocytosis,” is ubiquitous in tumors and mediates the suppression of innate immune inflammatory response. Considering the massive infiltrated macrophages in osteosarcoma, efferocytosis probably serves as a potential target, but is rarely studied in osteosarcoma. Here, we verified M2 polarization and PD-L1 expression of macrophages following efferocytosis. Pharmacological inhibition and genetic knockdown were used to explore the underlying pathway. Moreover, tumor progression and immune landscape were evaluated following inhibition of efferocytosis in osteosarcoma model. Our study indicated that efferocytosis promoted PD-L1 expression and M2 polarization of macrophages. Ëfferocytosis was mediated by MerTK receptor in osteosarcoma and regulated the phenotypes of macrophages through the p38/STAT3 pathway. By establishing the murine osteosarcoma model, we emphasized that inhibition of MerTK suppressed tumor growth and enhanced the T cell cytotoxic function by increasing the infiltration of CD8+ T cells and decreasing their exhaustion. Our findings demonstrate that MerTK-mediated efferocytosis promotes osteosarcoma progression by enhancing M2 polarization of macrophages and PD-L1-induced immune tolerance, which were regulated through the p38/STAT3 pathway.