Open AccessInterleukin-23 engineering improves CAR T cell function in solid tumors
Author(s) -
Xingcong Ma,
Peishun Shou,
Christof C. Smith,
Yuhui Chen,
Hongwei Du,
Chuang Sun,
Nancy P. Kren,
Daniel Michaud,
Sarah Ahn,
Benjamin G. Vincent,
Barbara Savoldo,
Yuliya Pylayeva-Gupta,
Shuqun Zhang,
Gianpietro Dotti,
Yingxin Xu
Publication year - 2020
Publication title -
nature biotechnology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.358
H-Index - 445
eISSN - 1546-1696
pISSN - 1087-0156
DOI - 10.1038/s41587-019-0398-2
Subject(s) - interleukin 21 , cytotoxic t cell , interleukin 3 , granzyme b , interleukin 12 , il 2 receptor , t cell , zap70 , antigen presenting cell , cytokine , autocrine signalling , chimeric antigen receptor , microbiology and biotechnology , natural killer t cell , chemistry , biology , cancer research , receptor , immunology , immune system , in vitro , biochemistry
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.