Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy

Abstract

Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regu-lating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

“…There is evidence for inhibitory functions of CD96, but the exact effect on human T-cells and NK cells is still not fully understood [ 19 ]. In human cancer, a correlation of CD96 with T-cell markers and PD-1 was shown.…”

“…Besides LAG-3 and Tim3, there are many other potentially therapeutically relevant immune checkpoints. T-cell immunoglobulin and ITIM domain (TIGIT) is a T-cell- and NK-cell-based inhibitory receptor [ 19 ]. The main TIGIT ligand, CD155, is expressed on tumor-infiltrating myeloid cells, macrophages and also tumor cells [ 20 ].…”

“…CD96 is another T- and NK-cell-based checkpoint receptor that can bind to CD155. While an inhibitory effect of CD96 is assumed based on mouse models, its function in human tissues still needs to be clarified [ 19 ]. The B- and T-lymphocyte attenuator receptor (BTLA) is an inhibitory receptor of B- and T-cells.…”

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

“…A further combination strategy to enhance antitumor mAb-triggered NK cell functions relies on the blockade of immune checkpoint inhibitory receptors. PD-1 or TIGIT blockade was shown to augment trastuzumab and cetuximab therapeutic efficacy in preclinical models and progressed to clinical trials in patients with advanced malignancies [35][36][37][182][183][184][185]; combinations aimed at blocking other immune checkpoints expressed in NK cells are currently under study and may soon approach the clinic [186] (Table 1 and Figure 1).…”

Antibody blockade of CD96 by distinct molecular mechanisms

“…2,3 Among them, TIGIT (WUCAM, VSIG9, VSTM3), CD96 (TACTILE), and CD112R (PVRIG) are immunoreceptors in the nectin family that have been identified as important regulators of immune responses. [4][5][6] These co-inhibitory receptors are expressed on T and natural killer cells, and their blockade has shown enhanced anti-tumor immune responses. [7][8][9] However, it has also been reported that CD96 has co-stimulatory rather than co-inhibitory activity.…”