目的:PD-1/PD-L1抑制剂已成为一种有前途的治疗方法。然而,宫颈癌(CC)患者的反应率低于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,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,免疫组化检测PD-L1、CD68和CD163的表达。生物信息学分析参与PD-L1调控的巨噬细胞亚型。建立共培养模型,观察TAMs对其形态学的影响,CC细胞的迁移和侵袭功能,以及TAMs对PD-L1的调控机制。
结果:PD-L1在肿瘤细胞上的表达可以预测患者的不良预后。PD-L1的表达与CD163+TAMs的浸润有很强的相关性。同样,生物信息学分析中PD-L1表达与M1/M2型TAMs浸润相关。细胞共培养结果显示M1/M2型TAMs能上调PD-L1的表达,特别是M2型TAM可能通过PI3K/AKT途径提高PD-L1的表达。同时,M1/M2型TAM可以影响形态变化,增强CC细胞的迁移和侵袭能力。
结论:PD-L1在肿瘤细胞中的表达可作为预后因素,且与CD163+TAMs浸润密切相关。此外,M2型TAMs可通过PI3K/AKT通路上调CC细胞PD-L1表达,增强迁移和入侵能力,并影响肿瘤进展。
OBJECTIVE: 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 CD163+TAMs 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 CD163+TAMs 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.