School of Life Sciences, University of Science and Technology of China, 230000 Hefei, China.
Chinese Academy of Sciences (CAS) Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163 Suzhou, China.
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6640-6650. doi: 10.1073/pnas.1921445117. Epub 2020 Mar 11.
The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.
程序性细胞死亡蛋白 1（PD-1）受体位于免疫细胞表面，是一种免疫检查点分子，介导肿瘤细胞的免疫逃逸。因此，针对 PD-1 的抗体已被证明在某些类型的癌症中能够增强 T 细胞的抗肿瘤活性。然而，PD-1 对肿瘤细胞的潜在影响在很大程度上仍然未知。在这里，我们表明 PD-1 在广泛的肿瘤细胞中表达。沉默 PD-1 或其配体 PD-1 配体 1（PD-L1）可促进体外细胞增殖和集落形成以及体内肿瘤生长。相反，PD-1 或 PD-L1 的过表达抑制肿瘤细胞增殖和集落形成。此外，针对 PD-1 或 PD-L1 的阻断抗体可促进细胞培养物和异种移植物中的肿瘤生长。从机制上讲，PD-1/PD-L1 的协调激活了其主要下游信号通路，包括 AKT 和 ERK1/2 通路，从而增强了肿瘤细胞的生长。这项研究表明，PD-1/PD-L1 是一种潜在的肿瘤抑制因子，可能调节对抗 PD-1/PD-L1 治疗的反应，因此代表了癌症免疫治疗的潜在生物标志物。
