Sweet Immune Checkpoint Targets to Enhance T Cell Therapy

Abstract

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.

Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma

“…Indeed, the lectin immune receptors that selectively sense and recognize these tumor associated structures have emerged as markers and possible therapeutic targets to dismantle the immunosuppressive networks [ 179 ].…”

Increased Level of Tim-3+PD-1+CD4+T Cells With Altered Function Might Be Associated With Lower Extremity Arteriosclerosis Obliterans

“…The blockade of Tim-3 and PD-1 pathways can suppress the proliferation and activation of CD4 + T cells and inhibit the Th2 bias but enhance the expression of IFN-g, TNF-a, and T-bet on CD4 + T cells. Immune checkpoint inhibitors are considered the standard of care for several cancers and chronic infections (16). Immune checkpoint inhibitors are monoclonal antibodies directed against coinhibitory molecules, in particular, CTLA-4, PD-1, and Tim-3.…”

“…In addition, the coexpression of these immune checkpoints on T cells identifies T cell subsets with a unique phenotype that could shape the inflammatory responses during many diseases. The blockade of these immune checkpoints to improve T cell responses is considered as a novel strategy for the treatment of chronic infections and some tumors (16,17).…”

Advances in the Immunomodulatory Properties of Glycoantigens in Cancer

“…Indeed, T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) binding to its ligand, galectin-9, results in Th1 cell death [135,136]. However, we will not discuss their functions in this work, since this information can be found in recent reviews [137][138][139][140][141].…”