Sweet Immune Checkpoint Targets to Enhance T Cell Therapy

Despite tremendous success against hematological malignancies, the performance of chimeric Ag receptor T cells against solid tumors remains poor. In such settings, the lack of success of this groundbreaking immunotherapy is in part mediated by ligand engagement of immune checkpoint molecules on the surface of T cells in the tumor microenvironment. Although CTLA-4 and programmed death-1 (PD-1) are well-established checkpoints that inhibit T cell activity, the engagement of glycans and glycan-binding proteins are a growing area of interest due to their immunomodulatory effects. This review discusses exemplary strategies to neutralize checkpoint molecules through an in-depth overview of genetic engineering approaches aimed at overcoming the inhibitory programmed death ligand-1 (PD-L1)/PD-1 axis in T cell therapies and summarizes current knowledge on glycoimmune interactions that mediate T cell immunosuppression.