Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy
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Antibody-based therapeutics targeting the inhibitory receptorsPD-1, PD-L1, or CTLA-4 have shown remarkable clinical progresson several cancers. However, most patients do not benefitfrom these therapies. Thus, many efforts are being made toidentify new immune checkpoint receptor-ligand pathways thatare alternative targets for cancer immunotherapies. Nectin andnectin-like molecules are widely expressed on several types oftumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are agroup of immunoglobulin superfamily receptors that interactwith Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals uponbinding their cognate ligands to the immune cells. The integratedsignals formed by their complex interactions contribute to regulatingimmune-cell functions. Several clinical trials are currentlyevaluating the efficacy of anti-TIGIT and anti-CD112R blockadesfor treating patients with solid tumors. However, manyquestions still need to be answered in order to fully understandthe dynamics and functions of these receptor networks. Thisreview addresses the rationale behind targeting TIGIT, CD226,CD96, and CD112R to regulate T- and NK-cell functions anddiscusses their potential application in cancer immunotherapy.
Abstract
Antibody-based therapeutics targeting the inhibitory receptorsPD-1, PD-L1, or CTLA-4 have shown remarkable clinical progresson several cancers. However, most patients do not benefitfrom these therapies. Thus, many efforts are being made toidentify new immune checkpoint receptor-ligand pathways thatare alternative targets for cancer immunotherapies. Nectin andnectin-like molecules are widely expressed on several types oftumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are agroup of immunoglobulin superfamily receptors that interactwith Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals uponbinding their cognate ligands to the immune cells. The integratedsignals formed by their complex interactions contribute to regulatingimmune-cell functions. Several clinical trials are currentlyevaluating the efficacy of anti-TIGIT and anti-CD112R blockadesfor treating patients with solid tumors. However, manyquestions still need to be answered in order to fully understandthe dynamics and functions of these receptor networks. Thisreview addresses the rationale behind targeting TIGIT, CD226,CD96, and CD112R to regulate T- and NK-cell functions anddiscusses their potential application in cancer immunotherapy.
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