Blocking Co-inhibitory Receptors: A Promising Cancer Immunotherapy strategy

The quality of T cell response, which is initiated through antigen recognition by the T cell receptor (TCR), is regulated by a balance between co-stimulatory and co-inhibitory signals. Under normal physiological conditions, co-inhibitory molecules are instrumental in preventing activation-induced cell death in T cells, maintaining self-tolerance, and reducing collateral damage to healthy tissue from the cytopathic effects of T cells and aberrant inflammation. Cancer cells can usurp these inhibitory pathways that the immune system uses to maintain self-tolerance and evade the anti-tumor immune responses. Given that CD8 + T cells have the capacity to recognize and kill the cognate antigen-expressing cell types, T cells have been the cornerstone of anti-tumor therapeutic interventions. Several co-inhibitory receptors have been identified and studied in cancer in past decades, including but not limited to PD-1, CTLA-4, LAG3, TIM3, TIGIT, and BTLA. They are named “immune checkpoints” referring to molecules that act as gatekeepers of immune responses. Co-inhibitory receptors are heavily expressed on a subset of T cells described as exhausted T cells (Tex) or dysfunctional T cells (Tdys). Dysfunctional T cells have reduced effector function and are generated in place of memory T cells when the T cells are chronically activated as in case of viral infection or in the tumor microenvironment (TME). Dysfunctional T cells in the TME prevent the establishment of durable immunological memory and permit tumor progression or relapse. Thus, targeting these dysfunctional T cells with antibody against co-inhibitory receptors is a promising strategy of cancer immunotherapy.