PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function

Abstract

Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8 þ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG-PVRL2 pathway is a nonredundant signaling node. A combination of PVRIG blockade with TIGIT or PD-1 blockade further increased T-cell activation. In human tumors, PVRIG expression on T cells was increased relative to normal tissue and trended with TIGIT and PD-1 expression. Tumor cells coexpressing PVR and PVRL2 were observed in multiple tumor types, with highest coexpression in endometrial cancers. Tumor cells expressing either PVR or PVRL2 were also present in numbers that varied with the cancer type, with ovarian cancers having the highest percentage of PVR À PVRL2 þ tumor cells and colorectal cancers having the highest percentage of PVR þ PVRL2 À cells. To demonstrate a role of PVRIG and TIGIT on tumor-derived T cells, we examined the effect of PVRIG and TIGIT blockade on human tumor-infiltrating lymphocytes. For some donors, blockade of PVRIG increased T-cell function, an effect enhanced by combination with TIGIT or PD-1 blockade. In summary, we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways. See related article on p. 244

TIGIT Blockade: A Multipronged Approach to Target the HIV Reservoir

“…Like TIGIT, TACTILE (CD96), and PVR-related Ig domain (PVRIG or CD112R) bind PVR, and PVRL2, respectively, whereas DNAM-1 (CD226) is a costimulatory counter receptor that competes with both TIGIT and TACTILE for PVR engagement and with PVRIG for PVRL2 binding (Figure 1) (Anderson et al, 2016;Zhu et al, 2016;Dougall et al, 2017;Xu et al, 2017;Sanchez-Correa et al, 2019). The inhibitory receptor PVRIG is expressed on activated T cells and NK cells (Figure 1), however, there is a lack of conclusive evidence in human NK cell studies as to whether TACTILE negatively or positively regulates activation (Fuchs et al, 2004;Georgiev et al, 2018;Whelan et al, 2019). Although PVR is a common ligand for TIGIT, TACTILE, and DNAM-1, the binding affinities vastly differ, with TIGIT having a greater affinity for PVR than either DNAM-1 or TACTILE (Figure 1) (Yu et al, 2009).…”

“…Strong interactions such as those between TIGIT and PVR or DNAM-1 in cis or PVRIG and PVRL2 are illustrated with heavy arrows. There is no clear consensus regarding whether TIGIT binds PVRL3 (dotted arrow) and it is unclear whether TIGIT/PVRL2 interactions are physiologically relevant in vivo (Stanietsky et al, 2009;Yu et al, 2009;Whelan et al, 2019). DNAM-1 interacts with both PVR and PVRL2 to counter inhibition, yet does so with lower affinity than either TIGIT or PVRIG.…”

Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer

“…As tumors progress, TIL become gradually exhausted, with increased expression of inhibitory receptors and reduced effector functions [ 33 ]. In EOC, CD8 + TIL express immune checkpoints (IC), including programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), T-cell immunoglobulin and mucin domain-containing (TIM)-3 [ 34 ], the lymphocyte-activation gene (LAG)-3 [ 35 ] and CD112R (PVRIG) [ 36 ]. We and others have demonstrated in EOC that, despite their exhausted status, CD8 + TIL exhibit a sustained potential for cytokine production and proliferation [ 34 , 37 ].…”

t(14;19)(q32;q13) IGH/Various Partners

“…NECTIN2 is composed of a signal peptide (amino acids 1-31), an extracellular domain (aa 32-360), a transmembrane domain (aa 361-381), and a cytoplasmic domain (aa 382-538). NECTIN2 also interacts with PVRIG CD226, CD96 to stimulate or inhibit lymphocyte cell signaling (Stamm et al, 2018;Whelan et al, 2019).…”