Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies

Figure 1

The factors involved in the development of CAR-T cell exhaustion. Persistent antigen from tumor cells interaction with TCR and CAR leads to hyperactivation, which drives expression of inhibitory receptors such as PD-1. Different costimulatory domains (such as CD28 and 4-1BB), epigenetic, and transcriptional profile modification are also involved in the process of CAR-T cell exhaustion. Immunoregulatory cells contribute to a tumor-supportive environment by producing suppressive cytokines such as IL-10 and TGF-β from Tregs that inhibit CAR-T cell activity and proliferation. Alteration of metabolic environment, including increase of adenosine by CD39 and CD73 in MDSCs, accumulation of kynurenine by IDO from tumor, limitation of arginine, and high level of glutamine, results in tumor cell survival and CAR-T cell dysfunction.