肿瘤细胞治疗研究
英文原题：PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function.
PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function.
PD-1/PD-L1轴在多种癌症免疫逃逸中的功能已被深入研究。
PD-1/PD-L1 轴在多种癌症免疫逃逸中的功能已被深入研究。然而，PD-L2 的潜在功能仍知之甚少。在此，我们证明 PD-L2 主要由透明细胞肾细胞癌（ccRCC）细胞以表面定位的方式表达于外泌体中。与 TDE-PD-L1 相比，肿瘤细胞来源外泌体 PD-L2（TDE-PD-L2）在多种癌症中呈高表达。在缺乏适应性免疫的情况下，TDE-PD-L2 抑制肿瘤生长和转移。在免疫健全条件下，TDE-PD-L2 以 PD-1 依赖的方式被免疫细胞劫持，通过增加调节性 T 细胞比例、减少细胞毒性 CD8+ T 细胞比例，在肿瘤浸润 T 细胞和脾脏中系统性抑制 T 细胞功能。靶向 PD-L2 的抗体可恢复 TDE-PD-L2 对肿瘤的作用。总之，我们证明 PD-1/TDE-PD-L2 轴系统性抑制 T 细胞功能，代表了一种潜在的 ccRCC 治疗策略。
The function of PD-1/PD-L1 axis have been intensively studied for immune escape of various cancers. However, the underlying function of PD-L2 remains poorly understood. Here, we demonstrate that PD-L2 is majorly expressed in exosomes with surface localization by clear cell renal cell carcinoma (ccRCC) cells. Tumor cell-derived exosome PD-L2 (TDE-PD-L2) exhibits high expression compared with TDE-PD-L1 in various cancers. In the absence of adaptive immune, TDE-PD-L2 suppresses tumor growth and metastasis. Under immune competence condition, TDE-PD-L2 is hijacked by immune cells in a PD-1-dependent manner to systematically dampen function of T cells via the increased proportion of the regulatory T cells and the decreased proportion of cytotoxic CD8 + T cells in both tumor-infiltrating T cells and spleen. The effects of TDE-PD-L2 on tumor is restored by antibodies targeting PD-L2. Collectively, we demonstrate that PD-1/TDE-PD-L2 axis systematically suppresses T cell functions, representing a potentially therapeutic strategy for ccRCC treatment.
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