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Distinct cytokines regulate gene expression and anti-tumor activity in regenerated CD8+ T cells derived-from induced pluripotent stem cells.

ABSTRACT: Adoptive T cell therapy can induce tumor regression in cancer patients. Tumor-specific CD8+ T cells regenerated from induced pluripotent stem cells (iPSCs), termed regenerated cytotoxic T lymphocytes (CTLs), are promising resources for adoptive T cell therapy. However, it remained unclear what kinds of cytokines enhance the anti-tumor activity of regenerated CTLs. In this study, we examined the effects of exogenous cytokines on the characteristics of regenerated CTLs. We found that IL-15- or IL-21-treatment in vitro enhanced the anti-tumor activity of regenerated CTLs, presumably by different mechanisms. IL-15-treated regenerated CTLs showed early-effector-like characteristics, whereas IL-21-treated regenerated CTLs showed both naïve- and effector-like characteristics. These findings provide useful insights for the clinical application of regenerated CTLs in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE265947 | GEO | 2026/04/02

REPOSITORIES: GEO

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Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naÃ¯ve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naÃ¯ve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison Comparitive analysis of cytokine effects on lymphocyte gene expression. GSM265712.gpr (S89_1_IL2_0.gpr): Cy3 - control, Cy5 - experimental GSM265713.gpr (S90_1_IL15_0.gpr): Cy3 - control, Cy5 - experimental GSM265714.gpr (S91_1_IL21_0.gpr): Cy3 - control, Cy5 - experimental GSM265715.gpr (S27_2_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265716.gpr (S29_2_0_IL15.gpr): Cy3 - experimental, Cy5 - control GSM265717.gpr (S30_2_0_IL21.gpr): Cy3 - experimental, Cy5 - control GSM265718.gpr (S31_3_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265719.gpr (S33_3_0_IL15.gpr): Cy3 - experimental, Cy5 - control

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Distinct cytokines regulate gene expression and anti-tumor activity in regenerated CD8+ T cells derived-from induced pluripotent stem cells.

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