Huang Lili, Yang Jingbo, Zhu Jinjin, Wang Huaishan, Dong Liyun, Guo Yeye, Chen Yeqing, Zhang Feng, Xu David J, Ou Lingling, Xu Jaiden R, Guan Lei, Doan Quoc D, Fan Andrew Y, Zhong Wenqun, Ko Jina, Liang Chengyu, Herlyn Meenhard, Guo Wei, Xu Xiaowei, Liu Shujing
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
Am J Pathol. 2025 Feb;195(2):306-320. doi: 10.1016/j.ajpath.2024.09.011. Epub 2024 Oct 29.
Tumor-associated macrophages (TAMs) play dual roles (both pro- and antitumor) in tumor progression. TAMs induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, CD163 and MRC1 levels were significantly elevated in metastatic melanomas compared with those in primary melanomas, correlating with CD274 expression and predicted patient clinical outcomes. To study the mechanisms regulating M2-like polarization, PD-L1 was knocked out in both YUMM1.7 and B16-F10 melanoma cells. Knocking out PD-L1 (PD-L1) in melanoma resulted in a decelerated in vivo growth rate, accompanied by a significantly increased M1/M2 ratio, more dendritic cells, and enhanced activation of CD8 T cells compared with wild-type (WT) melanoma cells. These alterations were associated with decreased expression of M2-associated chemokines (CCL2, CCL3, and CXCL2) and cytokines (IL6, IL10, and TGFB1). Mice harboring PD-L1 melanomas exhibited elevated levels of CD8 T cells in both the tumor-draining lymph nodes and the bloodstream compared with mice with PD-L1 melanomas. Treatment with extracellular vesicles (EVs) derived from PD-L1 melanoma resulted in a reduced tumor growth rate and fewer M2-like macrophages in the tumors compared with EVs from PD-L1 melanomas. Therefore, these data suggest that PD-L1 in melanoma and melanoma-derived EVs induces M2-like polarization, contributing to local and regional immune suppression.
肿瘤相关巨噬细胞（TAMs）在肿瘤进展中发挥双重作用（促肿瘤和抗肿瘤）。TAMs诱导癌细胞中程序性死亡配体-1（PD-L1）的表达。然而，PD-L1在黑色素瘤细胞中对TAM表型转换的调节作用仍未得到充分研究。在此，与原发性黑色素瘤相比，转移性黑色素瘤中CD163和MRC1水平显著升高，与CD274表达相关并可预测患者的临床结局。为了研究调节M2样极化的机制，在YUMM1.7和B16-F10黑色素瘤细胞中敲除了PD-L1。与野生型（WT）黑色素瘤细胞相比，在黑色素瘤中敲除PD-L1导致体内生长速率减慢，同时M1/M2比值显著增加，树突状细胞增多，CD8 T细胞活化增强。这些改变与M2相关趋化因子（CCL2、CCL3和CXCL2）和细胞因子（IL6、IL10和TGFB1）的表达降低有关。与携带PD-L1黑色素瘤的小鼠相比，携带PD-L1黑色素瘤的小鼠在肿瘤引流淋巴结和血液中的CD8 T细胞水平升高。与来自PD-L1黑色素瘤的细胞外囊泡（EVs）相比，用来自PD-L1黑色素瘤的EVs处理导致肿瘤生长速率降低，肿瘤中M2样巨噬细胞减少。因此，这些数据表明黑色素瘤和黑色素瘤衍生的EVs中的PD-L1诱导M2样极化，导致局部和区域免疫抑制。
