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

Abstract

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.

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

“…On the other hand, in a poorly infiltrating tumor, the majority of the available PD-1 molecules are those expressed by tumor cells that, if bound by a specific antibody, can promote tumor growth. Similar results were also obtained by Wang et al, who demonstrated that PD-1 inhibitory activity in tumor cells relies on AKT and ERK1/2 signaling pathways [ 129 ]. However, other studies, performed using melanoma and hepatocellular carcinoma models, described a completely different situation in which blocking PD-1 directly on cancer cells determined a marked reduction in tumor proliferation [ 130 , 131 ].…”

Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

“…The treatment of Calu-1, SW480, HT-29 and other cell lines with PD-1-targeted nivolumab, or pembrolizumab, increased cell proliferation and higher p-AKT and p-ERK levels than the cells treated with an isotype control antibody. The same observations were seen in xenografted cells in mice (10). The aforementioned results raise doubts about the adequacy of CRISPR-Cas9-mediated-PD-1 disruption in T cells (1,7).…”

“…The aforementioned results raise doubts about the adequacy of CRISPR-Cas9-mediated-PD-1 disruption in T cells (1,7). The clinical consequences of Wang et al (10) are unknown at this moment, however it offers a new view that the tumor cell intrinsic PD-1/PD-L1 axis suppresses tumor growth and inhibits AKT and ERK1/2 signaling pathways and could prevent the interaction with PD-1 expressing cells. As in cancer cells, PD-1 also regulates PI3K/AKT, MAPK/ERK1/2 and mammalian target of rapamycin (mTOR) pathways in T cells (9).…”

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

“…The lack of NKG2D ligands (MICA, MICB, or others) is a trait of resistant leukemia stem cells. Poly-ADP-ribose polymerase 1 (PARP1) represses the expression of NKG2D ligands and targeting resistant leukemia stem cells with PARP inhibitors could possibly restore the NK function [ 195 ]. Warfarin (an anticoagulant) interferes withGas 6, the ligand of TAM tyrosine kinase receptors, Tyro, AXL and Mer (TAM).…”