Knowns and Unknowns about CAR-T Cell Dysfunction

Abstract

Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation.

Keywords: CAR tonic signaling; CAR-T cell; T cell dysfunction; T cell exhaustion; T cell senescence; chimeric antigen receptor.

Figure 1

The landscape and evolution of T cell dysfunction. Depending on the priming condition (given at the bottom of the figure), the trajectory of the T cell development may be driven from naïve T cells to (1) anergic T cells; (2) memory T cells; (3) terminal effector T cells; and (4) exhausted T cells (Tex). Memory T cells remain susceptible to exhaustion. Tex cell pool includes progenitor Tex that are primarily responsive to PD-1 blockade and sustain proliferative potential. They give rise to nearly completely dysfunctional terminal Tex or (under certain circumstances) differentiate into highly cytotoxic Tex effector-like state. In some cancers, T cells with a typical progenitor Tex phenotype do not respond to checkpoint inhibition. Both terminally exhausted and effector/senescent T cells are characterized by negligible proliferation; however, the latter demonstrate significant cytotoxicity.

Figure 2

Factors affecting functionality, exhaustion, and senescence of CAR-T cells. PBMCs obtained through apheresis vary substantially in composition and quality. In particular, chemotherapy and older age may result in preemptive T cellular senescence. Apheresis product may be also enriched with Tregs or exhausted cells. These may significantly affect the final CAR-T cell product. At the same time, balanced CD4⁺/CD8⁺ composition and enrichment with naïve cells are known to be beneficial for cell functionality in the clinical setting. Finally, carefully validated CAR design and manufacturing process, e.g., IL-15/IL-7-based expansion, are essential in this context. On the contrary, chemotherapeutic treatment may lead to senescence and poor persistence of CAR-T cells. Several factors are in turn responsible for exhaustion/dysfunction of CAR-T cells in vivo.