PVRL2 Suppresses Antitumor Immunity through PVRIG-and TIGIT-independent Pathways

Sep 22, 2026

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Poliovirus receptor-related 2 (PVRL2, nectin-2/CD112) is identified as an immune checkpoint protein whose role is clarified by studying PVRL2 directly, rather than only its known receptor PVRIG. PVRL2 is highly expressed in tumor cells and tumor-derived exosomes, and its deletion in syngeneic mouse cancer models sharply reduces tumor growth in an immune-dependent manner, exceeding PD-L1 loss. Mechanistically, PVRL2 suppresses CD8+ T and NK activity in the tumor microenvironment via pathways independent of PVRIG, and TIGIT blockade plus PVRL2 deletion nearly abrogates tumor growth, supporting combinatorial cancer immunotherapy targeting.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Abstract

Introduction

Background: immune checkpoint inhibitors and resistance

Exosomes and immune suppression

Nectin/Nectin-like immune checkpoint pathway (PVRL2, PVR, TIGIT, PVRIG)

PVRL2 Suppresses Antitumor Immunity through PVRIGand TIGIT-independent Pathways Jiuling Yang1, Li Wang1, James R. Byrnes2, Lisa L. Kirkemo2, Hannah Driks1, Cassandra D. Belair1, Oscar A. Aguilar3, Lewis L. Lanier3, James A. Wells2, Lawrence Fong4, and Robert Blelloch1 ABSTRACT ◥ Poliovirus receptor-related 2 (PVRL2, also known as nectin-2 or CD112) is believed to act as an immune checkpoint protein in cancer;however, most insight into its role is inferred from studies on its known receptor, poliovirus receptor (PVR)-related immunoglobulin domain protein (PVRIG, also known as CD112R) . Here, we study PVRL2 itself. PVRL2 levels were found tobe high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer showed a dramatic reduction in tumor growth that was immune dependent. This effect was even greater than that seen with deletion of PD-L1 . PVRL2 was shown to function by suppressing CD8þ T and natural killer cells in the tumor microenvironment. The loss of PVRL2 suppressed tumor growth even in the absence of PVRIG. In contrast, PVRIG loss showed no additive effect in the absence of PVRL2 . T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade combined with PVRL2 deletion resulted in a near complete block in tumor growth. This effect was not recapitulated by the combined deletion of PVRL2 with its paralog, PVR, which is the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy. Introduction Over the past decade, immune checkpoint inhibitors (ICI), including antibodies blocking immune checkpoints PD-1, PDL1, and CTLA-4, have made substantial progress in advancing cancer immunotherapy. These ICIs enhance the ability of the host immune system to combat cancer and have achieved remarkable success across numerous cancer types. Nevertheless, only 10%–30% of patients with cancer exhibit favorable responses to these therapies (1–4) . Moreover, a majority of patients who initially respond eventually develop resistance during the course of treatment (1, 4) . The underlying mechanisms responsible for the initial or acquired resistance to ICIs in a large percentage of patients remain mostly unknown. Therefore, it is of utmost importance to gain a better understanding of these mechanisms and identify additional immunotherapeutic strategies to overcome resistance to further improve cancer care. Exosomes have emerged as a potential mechanism of resistance to ICIs (5–7) . Exosomes are small extracellular vesicles ranging from 50 to 150 nm in diameter that originate from the endosome system of almost all mammalian cells, including tumors cells (8) . Recent studies from our group and several others have demonstrated that tumor- 1Department of Urology, University of California San Francisco, San Francisco, California. 2Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California. 3Department of Microbiology and Immunology, University of California, San Francisco, and Parker Institute for Cancer Immunotherapy, San Francisco, California. 4Division of Hematology/ Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California. Corresponding Author: Robert Blelloch, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143 . E-mail: [robert.blelloch@ucsf.edu](robert.blelloch@ucsf.edu) Cancer Immunol Res 2024;12:575–91 doi: 10.1158/2326-6066 . CIR-23-0722 This open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license. 􀀁2024The Authors;Published by the American Association for Cancer Research derived exosomes can present PD-L1, thereby suppressing T-c

FAQs

What is the main finding about PVRL2 in antitumor immunity?

PVRL2 acts as a distinct inhibitor of the antitumor immune response. Its presence suppresses CD8+ T and natural killer cell activity in the tumor microenvironment, and its deletion markedly reduces tumor growth.

How does deleting PVRL2 compare with deleting PD-L1 or PVRIG?

In multiple syngeneic mouse models, PVRL2 deletion produces a dramatic reduction in tumor growth that is even greater than that seen with PD-L1 deletion. The reduction occurs even without PVRIG, and PVRIG loss shows no additive effect in the absence of PVRL2.

Why is combining TIGIT blockade with PVRL2 deletion highlighted?

Combining TIGIT blockade with PVRL2 deletion results in a near complete block in tumor growth. This strong effect is not reproduced by deleting PVRL2 together with its paralog PVR, the ligand for TIGIT.

Sep 22, 2026

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