Abstract
This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.
Highlights
Cellular immunotherapy, such as CAR-T, a therapy with T cells expressing antibody-based chimeric antigen receptor targeting tumor antigen, is an effective therapy against different types of hematological malignancies and against solid cancers [1,2]
The result of the above study shows the IL-2-dependent antagonistic effect of Treg cells [36] versus the agonistic IL-2-dependent effect of proliferative CD8+ T cells on anti-tumor activity of CD28-CD3ζ-CAR-T cells demonstrated by other groups [39,40,41], and demonstrates that the balance of Treg cells to effector cells ratio is an important marker of effective immunotherapy [40]
This report shows the complexity of T cell differentiation, stem cell memory, memory and effector functions, their regulatory, intracellular, extracellular markers, cellular signaling, metabolism, cytokine-directed regulation of T cell differentiation and function that should be considered during cellular immunotherapy, including CAR-T therapy
Summary
Cellular immunotherapy, such as CAR-T, a therapy with T cells expressing antibody-based chimeric antigen receptor targeting tumor antigen, is an effective therapy against different types of hematological malignancies and against solid cancers [1,2]. Theeach detailed mechanisms releases specific cytokines that can have either pro- or anti-inflammatory functions, survival or of T cell subset differentiation, T cell stem-like, memory, and effector functions is important for protective functions. All CD4+ Th subsets are differentiated from naive CD4+ T cells by specific cytokines: Th1 by IL-12 and IFN-γ (pro-inflammatory cytokine, with multiple roles such as increase of TLR (Toll-like receptor), induction of cytokine secretion or macrophage activation); Th-2 by IL-4; Treg by IL-2 and TGF-beta (Figure 2). IL-12 release by engineered CAR-T cells chronic autocytotoxicity in animals that received second generation CD19-specific CAR-T that should increased anti-cancer activity by recruiting macrophages [14]. Naive conventional T cells and regulatory T cells (effector and memory subtypes) differ in their extracellular, intracellular, epigenetic, and genetic markers, transcription factors, and metabolic pathways (discussed below) (Figure 3).
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