Overcoming intrinsic inhibitory pathways to augment the antineoplastic activity of adoptively transferred T cells: Re-tuning your CAR before hitting a rocky road

Abstract

Effector T cells become rapidly inactivated after antigen exposure due to extracellular as well as intrinsic signals. We have recently demonstrated that the deletion of diacylglycerol kinases, intrinsic inhibitors of T-cell signaling, enhances the activity of adoptively transferred T cells expressing a chimeric antigen receptor (CAR) specific for a tumor-associated antigen.

Keywords: Chimeric Antigen Receptor; T cell hypofunction; diacylglycerol kinase; tumor immunosuppression; tumor microenvironment.

Figure 1. Impact of diacylglycerol kinases on the antineoplastic activity of CAR-expressing T cells. (A) Obstacles for CAR-expressing T cells in tumor microenvironment. The tumor microenvironment is inhibitory for T cells and CAR-expressing T cells. At least in part, this results from: (1) the immunosuppressive effects of various tumor-infiltrating cells, (2) the inhibitory effects of tumor-derived soluble factors, (3) metabolic challenges, and (4) a microenvironment characterized by hypoxia and low pH. (B) DGKs are central inhibitors of TCR-mediated RAS/ERK signaling in functionally impaired T cells. Prolonged TCR signaling upregulates the expression of cell-intrinsic immunosuppressive factors such as diacylglycerol kinases (DGKs) and cbl-b. In functionally impaired T cells, high levels of DGKs mediate the phosphorylation of the second messenger diacylglycerol (DAG), blunting the activation of the RAS/ERK/AP-1 signaling pathway.