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Review
. 2021 Sep 17:11:723888.
doi: 10.3389/fonc.2021.723888. eCollection 2021.

Immunotherapeutic Potential of T Memory Stem Cells

Affiliations
Review

Immunotherapeutic Potential of T Memory Stem Cells

Yujie Li et al. Front Oncol. .

Abstract

Memory T cells include T memory stem cells (TSCM) and central memory T cells (TCM). Compared with effector memory T cells (TEM) and effector T cells (TEFF), they have better durability and anti-tumor immunity. Recent studies have shown that although TSCM has excellent self-renewal ability and versatility, if it is often exposed to antigens and inflammatory signals, TSCM will behave as a variety of inhibitory receptors such as PD-1, TIM-3 and LAG-3 expression, and metabolic changes from oxidative phosphorylation to glycolysis. These changes can lead to the exhaustion of T cells. Cumulative evidence in animal experiments shows that it is the least differentiated cell in the memory T lymphocyte system and is a central participant in many physiological and pathological processes in humans. It has a good clinical application prospect, so it is more and more important to study the factors affecting the formation of TSCM. This article summarizes and prospects the phenotypic and functional characteristics of TSCM, the regulation mechanism of formation, and its application in treatment of clinical diseases.

Keywords: HIV; T memory stem cells; autoimmune diseases; stemness; tumor immunotherapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Key discoveries on TSCM cells. GVHD, graft versus host disease; TSCM cells, T memory stem cells; HTLV-1, human T cell lymphotropic virus type 1; HIV-1, human immunodeficiency virus type 1; CAR-T, chimeric antigen receptor-engineered T cells; AML, acute myeloid leukemia; HSCT, hematopoietic stem cell transplantation.
Figure 2
Figure 2
Several strategies to induce the generation of TSCM. Activating T cells (CAR-T cells, TCR-T cells, TILs, VSTs) with anti-CD3/CD28 antibodies and co-cultivating them with cytokines or combined with PD-1 and LDH can promote the production of TSCM cells and change the expression levels of related anti-apoptotic proteins and metabolic molecules. In addition, the expression of TNF-α, IFN-γ, IL-2 and Granzyme B also increased significantly.
Figure 3
Figure 3
Influencing factors regulating oxidative metabolism of TSCM Cells. Inhibit glycolysis through different pathways and promote fatty acid oxidation (FAO)-dependent oxidative phosphorylation (OXPHOS). AQP9, Glycerol channel aquaporin 9; AMPK, AMP-activated protein kinase; TAG, triglyceride; mTORC1, Rapamycin Complex 1.
Figure 4
Figure 4
Possible developmental trajectory of exhausted T cells and the comparison and relationship with memory or effector T cells. Under continuous antigen stimulation, T cells transform from precursor exhausted cells into terminally exhausted T cell populations, which mainly depends on the expression of the transcription factor TCF-1, accompanied by the high expression of a variety of inhibitory receptors. The relationship between the differentiation of T cell subsets and exhausted T cells remains to be explored. PD-1, PD ligand 1; TCF1, T cell factor-1; TIM-3, T-cell immunoglobulin domain and mucin domain protein 3; LAG-3, lymphocyte activation gene 3; TOX, thymocyte selection-associated high-motility group (HMG) box protein.
Figure 5
Figure 5
Target TSCM cells to treat human diseases. TSCM cells can exacerbate human disease. Left, treat TSCM-driven diseases, such as autoimmune diseases, HIV, etc., by blocking the production of TSCM. The expression of CCR5 promotes the infection of TSCM cells with HIV. Viral restriction factors and vaccines can target TSCM cells to treat HIV. Blocking the mTORC1 pathway promotes the self-renewal and differentiation of TSCM. Right, TSCM cells are expanded in vitro by adding cytokines, CAR modification, immune checkpoint blocking, and gene editing. Stars represent cells latently infected with HIV.

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