Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 12; pp. 6640 - 6650
• Main Authors: Wang, Xiaodong, Yang, Xiaohui, Zhang, Chang, Wang, Yang, Cheng, Tianyou, Duan, Liqiang, Tong, Zhou, Tan, Shuguang, Zhang, Hangjie, Saw, Phei Er, Gu, Yinmin, Wang, Jinhua, Zhang, Yibi, Shang, Lina, Liu, Yajuan, Jiang, Siyuan, Yan, Bingxue, Li, Rong, Yang, Yue, Yu, Jie, Chen, Yunzhao, Gao, George Fu, Ye, Qinong, Gao, Shan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.03.2020
• Subjects: AKT protein; Antibodies; Anticancer properties; Antitumor activity; Apoptosis; Biological Sciences; Biomarkers; Blocking antibodies; Cell death; Cell growth; Cell proliferation; Colonies; Immune checkpoint; Immune system; Ligands; Lymphocytes; Lymphocytes T; PD-1 protein; PD-L1 protein; Tumor cells; Tumor suppressor genes; Tumors; Xenografts; Xenotransplantation; tumor cell-intrinsic PD-L1; tumor suppressor; drug resistance; biomarker; tumor cell-intrinsic PD-1
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1921445117

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.