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].