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. 2021 Feb 3;13(4):598. doi: 10.3390/cancers13040598

Figure 2.

Figure 2

Interventions aiming at limiting T-cell dysfunction for adoptive immunotherapy. (A) Conventional αβ T cells are generally stimulated with specific peptides that may be presented by professional antigen-presenting cells such as dendritic cells (DCs) and supported by IL-2 supplementation and/or other cytokines. However, repetitive or chronic antigen stimulation promotes the gradual accumulation of dysfunctional cells over time. Many interventions are under investigation to maintain the cells in a less differentiated state. A shorter culture time allows for the maintenance of a higher percentage of healthy cells, but this may limit the number of cells manufactured. The addition of various factors to promote a memory phenotype differentiation is also evaluated, including the use of IL-21, TGFβ, histone deacetylase (HDAC) inhibitors, or AKT inhibitors. The rejuvenation of dysfunctional T cells by induced pluripotent stem cell technology can also generate less differentiated cells. (B) Unconventional γδ T cells are stimulated with amino-bisphosphonates and phosphoantigens, combined with IL-2. The pre-selection of T cells with a favorable phenotype, excluding cells expressing inhibitory receptors such as PD-1, has been investigated to limit the development of dysfunctional features. (C) Natural killer (NK) cells are mainly activated with IL-2 and feeder cells. Supplementation with various cytokines or agonists of co-stimulatory molecules (e.g., 4-1BB) can shape their differentiation status and modulate their receptor expression pattern. The engineering of feeder cells as well as the NK cells themselves to express these factors is also underway. (D) Tumor-infiltrating lymphocytes are stimulated with anti-CD3 with or without anti-CD28, with IL-2 supplementation. As for conventional T cells, the addition of various cytokines can promote a memory phenotype differentiation. The combination of a 4-1BB agonist and PD-1 blockade can also prevent the development of dysfunction. Inhibition of p38MAPK signaling has further shown to limit development of senescence features. This figure was created with BioRender.com.