CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：GPR55 in the tumor microenvironment of pancreatic cancer controls tumorigenesis.
GPR55 in the tumor microenvironment of pancreatic cancer controls tumorigenesis.
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我们的研究表明，在 PDAC 模型中，TME 细胞中的 GPR55 可能通过抑制 T 细胞功能（如迁移）来驱动肿瘤生长，使其成为免疫治疗的一个有趣靶点。
G蛋白偶联受体55（GPR55）是扩展的内源性大麻素系统（ECS）的一部分，在包括胰腺癌在内的不同癌症模型中发挥促肿瘤作用。除癌细胞外，免疫肿瘤微环境（TME）中的多种细胞也表达ECS受体，这些受体对肿瘤生长具有关键决定作用。GPR55在癌细胞中的作用已被广泛描述，但其在免疫TME中的作用尚不明确。
我们旨在胰腺导管腺癌（PDAC）模型中揭示GPR55在肿瘤免疫中的作用。为此，将小鼠PDAC来源的KPCY肿瘤细胞系或过表达GPR55的KPCY细胞系（KPCY55）皮下注射到野生型（WT）和GPR55敲除（KO）小鼠中，并通过流式细胞术评估免疫细胞群体。
TME中GPR55的缺失导致肿瘤重量和体积减少，并改变了肿瘤的免疫细胞组成，通过增加CD3+ T细胞、特别是CD8+ T细胞的数量以及巨噬细胞上PDL1的表达，有利于形成抗肿瘤环境。RNA-seq通路分析显示，与WT小鼠相比，GPR55 KO小鼠的KPCY55肿瘤中T细胞活性更高。此外，GPR55 KO小鼠的肿瘤中T细胞趋化因子Cxcl9和Cxcl10水平升高。与WT小鼠的T细胞相比，GPR55 KO小鼠的T细胞向CXCL9的迁移增加，表明CXCR3/CXCL9轴参与了T细胞向GPR55 KO小鼠肿瘤的流入。值得注意的是，抗PD-1免疫治疗增加了WT小鼠的肿瘤负荷，而这一效应在GPR55 KO小鼠中不存在。
The G protein-coupled receptor 55 (GPR55) is part of an expanded endocannabinoid system (ECS), and plays a pro-tumorigenic role in different cancer models, including pancreatic cancer. Next to cancer cells, various cells of the immune tumor microenvironment (TME) express receptors of the ECS that critically determine tumor growth. The role of GPR55 in cancer cells has been widely described, but its role in the immune TME is not well understood.
We intended to uncover the role of GPR55 in tumor immunity in a model of pancreatic ductal adenocarcinoma (PDAC). To this end, a KPCY tumor cell line or a GPR55-overexpressing KPCY cell line (KPCY55) from murine PDAC were subcutaneously injected into wildtype (WT) and GPR55 knockout (KO) mice, and immune cell populations were evaluated by flow cytometry.
Deficiency of GPR55 in the TME led to reduced tumor weight and volume, and altered the immune cell composition of tumors, favoring an anti-tumorigenic environment by increasing the number of CD3 + T cells, particularly CD8 + T cells, and the expression of PDL1 on macrophages. RNA-seq pathway analysis revealed higher T cell activity in KPCY55 tumors of GPR55 KO vs. WT mice. In addition, tumors from GPR55 KO mice displayed increased levels of T cell chemokines Cxcl9 and Cxcl10. Migration of T cells from GPR55 KO mice towards CXCL9 was increased in comparison to T cells from WT mice, suggesting that a CXCR3/CXCL9 axis was involved in T cell influx into tumors of GPR55 KO mice. Notably, anti-PD-1 immunotherapy increased tumor burden in WT mice, while this effect was absent in the GPR55 KO mice.
Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies.
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