CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer
CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer
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DOI：
10.1096/fj.202201982rrr
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发表时间：
2023-09
期刊：
影响因子：
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通讯作者：
Ying Shao;Yan Lan;Xinyue Chai;Shuhua Gao;Jinxiu Zheng;Rui Huang;Yu Shi;Yi Xiang;
中科院分区：
文献类型：
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作者：
Ying Shao;Yan Lan;Xinyue Chai;Shuhua Gao;Jinxiu Zheng;Rui Huang;Yu Shi;Yi Xiang;
结直肠癌（CRC）患者的免疫治疗预后不良，因此需要全面了解肿瘤微环境（TME）内的免疫抑制机制。毫无疑问，抗肿瘤免疫细胞在免疫耐受中发挥着不可或缺的作用。因此，研究具有增强抗肿瘤免疫力能力的新型免疫相关因子势在必行。在这里，我们利用 R 和 Cytoscape 进行生物信息分析，以鉴定在 CRC 恶性进展过程中在 CRC 中过度表达的枢纽基因趋化因子（C-X-C 基序）配体 8 (CXCL8)。然而，CXCL8在CRC免疫中的具体作用仍有待阐明。为此，我们评估了肿瘤来源的 CXCL8 如何通过体内和体外促进 M2 巨噬细胞浸润，这可以由 TME 内的 IL-1β 触发。从机制上讲，CXCL8 诱导的 M2 巨噬细胞极化取决于 STAT3 信号传导的激活。最后，免疫组织化学和多重免疫组织化学分析发现，CXCL8 不仅增强 PD-L1+ M2 巨噬细胞浸润，而且还能减弱小鼠 CRC 模型中 PD-1+CD8+ T 细胞的募集。总之，这些发现强调了 CXCL8 在促进 M2 巨噬细胞极化和抑制 CD8+ T 细胞浸润方面的关键作用，从而将 CXCL8 与促进肿瘤逃避的免疫抑制微环境的紧急情况联系起来。总的来说，这些发现可能为结直肠癌免疫治疗提供新策略。
The poor prognosis of immunotherapy in patients with colorectal cancer (CRC) necessitates a comprehensive understanding of the immunosuppressive mechanisms within tumor microenvironment (TME). Undoubtedly, the anti‐tumor immune cells play an indispensable role in immune tolerance. Therefore, it is imperative to investigate novel immune‐related factors that have the capacity to enhance anti‐tumor immunity. Here, we employed bioinformatic analysis using R and Cytoscape to identify the hub gene chemokine (C‐X‐C motif) ligand 8 (CXCL8), which is overexpressed in CRC, in the malignant progression of CRC. However, its specific role of CXCL8 in CRC immunity remains to be elucidated. For this purpose, we evaluated how tumor‐derived CXCL8 promotes M2 macrophage infiltration by in vivo and in vitro, which can be triggered by IL‐1β within TME. Mechanistically, CXCL8‐induced polarization of M2 macrophages depends on the activation of the STAT3 signaling. Finally, immunohistochemistry and multiplexed immunohistochemistry analysis identified that CXCL8 not only enhances PD‐L1+ M2 macrophage infiltration but also attenuates the recruitment of PD‐1+CD8+ T cells in murine CRC models. Together, these findings emphasize the critical role for CXCL8 in promoting M2 macrophage polarization and inhibiting CD8+ T cell infiltration, thereby links CXCL8 to the emergency of immunosuppressive microenvironment facilitating tumor evasion. Overall, these findings may provide novel strategy for CRC immunotherapy.