Increased CD112 Expression in Methylcholanthrene-Induced Tumors in CD155-Deficient Mice

Abstract

Tumor recognition by immune effector cells is mediated by antigen receptors and a variety of adhesion and costimulatory molecules. The evidence accumulated since the identification of CD155 and CD112 as ligands for DNAM-1 in humans and mice has suggested that the interactions between DNAM-1 and its ligands play an important role in T cell– and natural killer (NK) cell–mediated recognition and lysis of tumor cells. We have previously demonstrated that methylcholanthrane (MCA) accelerates tumor development in DNAM-1–deficient mice, and the Cd155 level on MCA-induced tumors is significantly higher in DNAM-1–deficient mice than in wild-type (WT) mice. By contrast, Cd112 expression on the tumors is similar in WT and DNAM-1-deficient mice, suggesting that CD155 plays a major role as a DNAM-1 ligand in activation of T cells and NK cells for tumor immune surveillance. To address this hypothesis, we examined MCA-induced tumor development in CD155-deficient mice. Unexpectedly, we observed no significant difference in tumor development between WT and CD155-deficient mice. Instead, we found that Cd112 expression was significantly higher in the MCA-induced tumors of CD155-deficient mice than in those of WT mice. We also observed higher expression of DNAM-1 and lower expression of an inhibitory receptor, TIGIT, on CD8+ T cells in CD155-deficient mice. These results suggest that modulation of the expression of receptors and CD112 compensates for CD155 deficiency in immune surveillance against MCA-induced tumors.

TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy

“…Recent studies looked at the role of CD155 in MCA-induced tumors and were not able to show any difference in tumor growth in the absence of CD155. 53 Interestingly, they found that CD112 expression was upregulated in CD155-deficient mice suggesting that the two ligands can redundantly regulate T-cell responses to maintain suppression of the immune response. 53 This could be due to preferential interaction of TIGIT with CD112.…”

“…53 Interestingly, they found that CD112 expression was upregulated in CD155-deficient mice suggesting that the two ligands can redundantly regulate T-cell responses to maintain suppression of the immune response. 53 This could be due to preferential interaction of TIGIT with CD112. However, the TIGIT-CD112 interaction is not very strong.…”

Critical roles of co‐activation receptor DNAX accessory molecule‐1 in natural killer cell immunity

“…Similar to findings regarding NKG2D ligands, over‐expression of DNAM‐1Ls is considered a critical danger signal that alerts cytotoxic cells to combat tumour cells. Therefore, CD155 appears to play dual roles in eliminating and promoting tumours …”

“…Therefore, CD155 appears to play dual roles in eliminating and promoting tumours. 74 The induction of DNAM-1L expression on tumour cells is a promising therapeutic strategy for cancer. The DNAM-1 receptor system has already been used as a target for anti-cancer therapies.…”

Influence of tumor cells on natural killer cell phenotype and cytotoxicity

“…Distinctive examples are DNAM-1, TIGIT, and CD96, all critical regulators of NK cell function which share CD155 and CD112 ligands (members of nectin and nectin-like protein families) [10]. CD155 is a dominant ligand over CD112 for DNAM-1 and TIGIT [11]. CD155 (Necl5, PVR, Tage4) is an immunoglobulin-like receptor found on certain tumors [10,12,13].…”