Optimal Avidity of the Immune Synapse and Mitochondrial Repair Trigger Asymmetrical Cell Division and CAR T Cell...

Chimeric antigen receptor (CAR) T cell persistence with memory is the current research focus of cancer immunotherapy. The incomplete effect of CAR T cells against tumors results from CAR T cell dysfunction and exhaustion. Asymmetric cell division is an evolutionarily conserved mechanism to maintain mother stem cells during embryonic development, and for immune cells to provide a continuous supply of diverse populations to fight infections and cancer. CAR T cells use ACD to determine their fate during the first mitotic division after interaction with its target, creating a pool of memory CAR T cells which can be recalled to be effector cells during tumor relapse, necessarily to offset the diminished ability of exhausted CAR T cells in controlling the tumor. Affinity of the CAR T - target cell immune synapse and mitochondrial dynamics regulate ACD. We review the literature regarding CAR T cell persistence, exhaustion, and mechanisms of reversing exhaustion. Subsequently, we present a hypothesis linking mitophagy to CAR T cell exhaustion, modulation of which may be clinically relevant in the treatment of cancers with CAR T cells.