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Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.

ABSTRACT: Tumor-specific CD8 T cells often fail to elicit effective antitumor immune responses due to an inability to expand into a substantial effector population and persist long-term in vivo. Using an adoptive transfer model of cancer immunotherapy, we demonstrate that constitutive eomesodermin (Eomes) expression in tumor-specific CD8 T cells improves tumor rejection and survival. The increase in tumor rejection was associated with an increased number and persistence of CD8 T cells in lymphoid tissues during acute tumor rejection, tumor regrowth, and in mice that remained tumor-free. Constitutive Eomes expression increased expression of CD25, and this was associated with enhanced interleukin-2 responsiveness and tumor-specific CD8 T-cell proliferation. Moreover, constitutive Eomes expression improved cell survival. Taken together, our data suggest that constitutive Eomes expression enhances CD8 T-cell proliferation and survival, in part through the enhancement of interleukin-2 responsiveness through CD25 induction.

SUBMITTER: Furusawa A

PROVIDER: S-EPMC5801069 | biostudies-literature | 2018 Feb/Mar

REPOSITORIES: biostudies-literature

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Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.

Furusawa Aki A Reiser John J Sadashivaiah Kavitha K Simpson Haley H Banerjee Arnob A

Journal of immunotherapy (Hagerstown, Md. : 1997) 20180201 2

Tumor-specific CD8 T cells often fail to elicit effective antitumor immune responses due to an inability to expand into a substantial effector population and persist long-term in vivo. Using an adoptive transfer model of cancer immunotherapy, we demonstrate that constitutive eomesodermin (Eomes) expression in tumor-specific CD8 T cells improves tumor rejection and survival. The increase in tumor rejection was associated with an increased number and persistence of CD8 T cells in lymphoid tissues ...[more]

PMID: 29271784

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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

Dataset Information

Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.

Publications

Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy.

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