M2 型肿瘤相关巨噬细胞通过 PI3K/AKT 通路上调宫颈癌中 PD-L1 的表达。

BACKGROUND AND PURPOSE: PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression. METHODS: The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1. RESULTS: PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells. CONCLUSIONS: PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

背景与目的：PD-1/PD-L1 抑制剂已成为一种有前途的治疗方法。然而，在宫颈癌（CC）患者中的反应率低于 30%，这与肿瘤微环境（TME）中的免疫抑制成分有关。肿瘤相关巨噬细胞（TAMs）作为最重要的免疫细胞之一，参与肿瘤抑制微环境的形成。因此，研究 TAMs 对 PD-L1 表达的调控机制将为提高疗效提供理论依据。

方法：收集 CC 患者的临床资料和病理组织，采用免疫组织化学法检测 PD-L1、CD68 和 CD163 的表达。采用生物信息学方法分析参与 PD-L1 调节的巨噬细胞亚型。建立共培养模型，观察 TAMs 对 CC 细胞形态、迁移和侵袭功能的影响，以及 TAMs 对 PD-L1 的调控机制。

结果：肿瘤细胞上的 PD-L1 表达可预测患者的预后不良。并且 PD-L1 表达与 CD163TAMs 浸润之间存在很强的相关性。同样，在生物信息学分析中，PD-L1 表达与 M1/M2 型 TAMs 浸润相关。细胞共培养结果表明，M1/M2 型 TAMs 可上调 PD-L1 表达，尤其是 M2 型 TAMs 可能通过 PI3K/AKT 通路上调 PD-L1 表达。同时，M1/M2 型 TAMs 可影响 CC 细胞的形态变化，并增强其迁移和侵袭能力。

结论：肿瘤细胞中的 PD-L1 表达可作为预后因素，与 CD163TAMs 浸润密切相关。此外，M2 型 TAMs 可通过 PI3K/AKT 通路上调 CC 细胞中的 PD-L1 表达，增强其迁移和侵袭能力，并影响肿瘤进展。