Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy.

Han Yao,Jie Xu,Huanbin Wang,Chushu Li,Jing-Yuan Fang

doi:10.3389/fimmu.2018.01774

Abstract

Programmed death 1 (PD-1) and its two natural ligands PD-L1 and PD-L2 are responsible for delivering inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. In previous studies, PD-1 was found only expressed on the surface of immune cells, such as T cells and B cells while PD-1’s ligands PD-L1 and PD-L2 were found expressed in some tumor cells. However, recent studies revealed intrinsic expression of PD-1 in melanoma and some other cancers. In melanoma cells, PD-1 can be activated by its ligand PD-L1 expressed by tumor cells, modulating downstream mammalian target of rapamycin signaling and promoting tumor growth independent of adaptive immunity. In addition to melanoma, PD-1 was also detected in liver cancer cells as well as in non-small lung cancer cells. Unlike its oncogenic functions in melanoma and hepatic carcinoma cells, PD-1 seemed to play a distinct role in lung cancer, as blockade of PD-1 instead promoted tumor cells proliferation. Tumor-intrinsic PD-1 expression seems to be widespread in many tumor types, according to our reanalysis on cancer transcriptomic and proteomic data. The multifaceted roles of PD-1 in tumor cells beyond immune checkpoint signaling may explain the differential therapeutic effects of anti-PD-1 and anti-PD-L1 drugs and provide crucial information when developing combinatorial approaches to enhance antitumor immunity.

Highlights

As the second generation clinical target of immune checkpoint, programmed death 1 (PD-1) is protein of the CD28 superfamily and a kind of cell membrane protein with 288 amino acids [1]
This review summarizes our recent understanding on the multifaceted roles of tumor cellintrinsic Programmed death 1 (PD-1), aiming to present this interesting research topic to the attentions of researchers in the field of immunotherapy
By obtaining and preprocessing the mRNA expression data from The Cancer Genomic Atlas (TCGA) project [33], we have summarized the expression of PD-1 in the tissues of 17 cancer types (Figure 4A)

Summary

INTRODUCTION

As the second generation clinical target of immune checkpoint, programmed death 1 (PD-1) is protein of the CD28 superfamily and a kind of cell membrane protein with 288 amino acids [1]. PD-1 blockade and knockdown (KD) in vitro and in vivo inhibited tumor growth independently of adaptive immunity In these tumor cells, the cytosolic domains of PD-1 was found to interact with the eukaryotic initiation factor 4E and RPS6, promoting the phosphorylation of these mTOR effector proteins (Figure 1) [20]. In support to this proposed model, combination of mTOR inhibitors and PD-1 antibody provided more durable and synergistic tumor regression than either single agent alone, each of which presented only modest efficacy. It suggested the possibility that anti-PD-1 immunotherapy will be rendered less efficacious or even deleterious in some patient and it is very necessary to elucidate the mechanism how cell-intrinsic PD-1 regulates tumor growth and development in different tumors

IMPLICATIONS IN REFINING COMBINATORIAL IMMUNOTHERAPIES

Findings

CONCLUSION