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- Title
Knowns and Unknowns about CAR-T Cell Dysfunction.
- Authors
Titov, Aleksei; Kaminskiy, Yaroslav; Ganeeva, Irina; Zmievskaya, Ekaterina; Valiullina, Aygul; Rakhmatullina, Aygul; Petukhov, Alexey; Miftakhova, Regina; Rizvanov, Albert; Bulatov, Emil
- Abstract
Simple Summary: The primary issue of adoptive cell therapy is the poor in vivo persistence. In this context, it is necessary to clarify the fundamental mechanisms of T cell dysfunction. Here we review common dysfunctional states, including exhaustion and senescence, and discuss the challenges associated with phenotypical characterization of these T cell subsets. We overview the heterogeneity among exhausted T cells as well as mechanisms by which T cells get reinvigorated by checkpoint inhibitors. We emphasize that some cancers not responding to such treatment may activate distinct T cell dysfunction programs. Finally, we describe the dysfunction-promoting mechanisms specific for CAR-T cells and the ways to mitigate them. 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.
- Subjects
CELLULAR therapy; CELL receptors; CELLULAR aging; CELLULAR signal transduction; TUMORS; T cells; EPIGENOMICS; IMMUNOTHERAPY
- Publication
Cancers, 2022, Vol 14, Issue 4, p1078
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers14041078