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Nat Biotechnol ; 38(4): 448-459, 2020 04.
Article in English | MEDLINE | ID: mdl-32015548

ABSTRACT

Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23α p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR T cells showed superior efficacy in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15.


Subject(s)
Immunotherapy, Adoptive/methods , Interleukin-23/metabolism , Neoplasms/therapy , T-Lymphocytes/immunology , Animals , Cell Hypoxia/genetics , Cell Line, Tumor , Cell Proliferation , Humans , Interleukin-12 Subunit p40/genetics , Interleukin-12 Subunit p40/metabolism , Interleukin-23/genetics , Lymphocyte Activation , Mice , Neoplasms/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Receptors, Interleukin/genetics , Receptors, Interleukin/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/genetics , T-Lymphocytes/metabolism , Xenograft Model Antitumor Assays
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