Physiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor microenvironment through expression of cognate ligands for the ICs present on the cell surface of CD8+ T lymphocytes. The ligation of ICs on CD8+ T lymphocytes triggers inhibitory signaling pathways, leading to quiescence or an exhaustion of CD8+ T lymphocytes. This results in failure of immunotherapy. To overcome this, several FDA-approved therapeutic antibodies are available, but the clinical outcome is quite variable due to the resistance encountered through upregulated expression of alternate ICs such as VISTA, LAG-3, TIGIT and TIM-3. This review focuses on the roles played by the traditional as well as alternate ICs and the contribution of associated signaling pathways in generating such resistance to immunotherapy. Combinatorial targeting of traditional and alternate ICs might be beneficial for immune-refractory tumors.
Keywords: CD8+ T lymphocytes; CTLA-4; LAG-3; PD-1; TIGIT; TIM-3; VISTA; immune checkpoints; immuno-refractory tumors; immunosuppression; immunotherapy.