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C-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2–independent costimulation

ABSTRACT: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy for solid tumors necessitates engineering strategies to promote functional persistence in an immunosuppressive environment. Herein, we exploit c-KIT signaling - a physiological pathway associated with stemness in hematopoietic progenitor cells with loss of expression during T-cell differentiation. CAR T cells with intracellular but no cell-surface receptor expression of c-Kit D816V mutation, KITv, show upregulated STAT phosphorylation, antigen-activation dependent proliferation, and susceptibility to tyrosine kinase inhibitors. KITv signaling provides CD28, IL-2-independent, and IFN-γ-mediated costimulation augmenting cytotoxicity of antigen-activated first-generation CAR T cells that translates to enhanced survival, including in TGF-β-rich and low antigen-expressing solid tumor models. KITv CAR T cells demonstrate equivalent or higher in vivo efficacy compared to second-generation CAR T cells, and further enhance efficacy as signal 3 when combined with CD28 costimulation, providing a potent approach to treat solid tumors by adoptive cell therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207754 | GEO | 2025/07/01

REPOSITORIES: GEO

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c-Kit signaling potentiates CAR T-cell efficacy in solid tumors by CD28- and IL-2–independent costimulation

Project description:The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we exploit c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression—but no cell-surface receptor expression—of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen-activation-dependent proliferation, CD28- and IL-2–independent and IFN-γ–mediated costimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in TGF-β–rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 costimulation, KITv costimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.

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c-Kit signaling potentiates CAR T-cell efficacy in solid tumors by CD28- and IL-2–independent costimulation

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Effect of costimulation on microRNAs levels in human naïve CD4 T cells

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