2.10 CD112R (PVRIG: Poliovirus receptor-related immunoglobulin domain-containing)
CD112R, also known as PVRIG (Poliovirus receptor-related immunoglobulin domain-protein), is an emerging immune checkpoint receptor that plays a significant role in regulating immune responses, particularly in the context of cancer immunotherapy. It is a type I transmembrane glycoprotein expressed on various immune cells, including T cells, natural killer (NK) cells, and subsets of myeloid cells [241, 242]. It was initially named and described by Zhu et al. in 2016 [241]. The primary ligand for CD112R is CD112 (PVRL2, nectin-2), a member of the nectin family of adhesion molecules. CD112 is expressed on both tumor cells and antigen-presenting cells (APCs), where it serves as a binding partner for CD112R. The interaction between CD112R and CD112 delivers inhibitory signals that modulate immune cell activation and effector functions [242].
In cancer, CD112R expression has been observed on exhausted T cells and dysfunctional NK cells within the TME. Studies have shown that CD112R exhibits high expression on NK cells in ovarian, endometrial, kidney, prostate, lung, and breast cancers [243]. In a group of 60 ovarian cancer patients, elevated CD112 expression correlated with lymph node metastasis and residual tumor presence following surgery [243]. High expression of CD112R has also been noted in liver metastases from colorectal cancer [244]. Karabulut et al. noted that serum levels of CD112R have diagnostic value, with higher levels correlating with an adverse prognostic impact on progression-free survival (PFS) in patients with early-stage colorectal carcinoma [245]. A study by Murter et al. showed that enhanced CD8+ T-cell effector function inhibited tumor growth more effectively in PVRIG-/- mice compared to wild-type mice [246]. Preclinical studies have demonstrated that CD112R blockade independently or in combination with other therapy, can lead to enhanced cytotoxicity and cytokine production by T cells and NK cells, which are crucial for recognizing and eliminating cancer cells. Blocking CD112R enhanced T-cell function, in an ex vivo study using tumor-derived T cells. When combined with TIGIT or PD-1 blockade, this effect was further enhanced [247]. A preclinical study by Xue et al. noted that, IBI352g4a, a novel humanized anti-PVRIG antibody with Fc-competent function, induced significant NK cell activation in TILs (single dose), and also T-cell activation was observed after the second dose by blocking the interaction between PVRIG and its ligand PVRL2 [248]. Blockade of CD112R separately, or in combination with TIGIT signaling sensitizes human natural killer cell functions in post-trastuzumab therapy resistant breast cancer [249]. Clinical trials are currently underway to evaluate the safety, efficacy, and therapeutic potential of CD112R inhibitors (NCT04570839 PVRIG inhibitor + BMS-986207 (TIGIT inhibitor) and nivolumab ) (NCT03667716, CD112R inhibitor (COM701) +/- PD-1) [10].