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.

刺激 T 细胞增殖的细胞因子，例如白细胞介素 (IL)-15，已被探索作为增强嵌合抗原受体 (CAR) T 细胞抗肿瘤活性的一种手段。然而，T 细胞中的组成型细胞因子信号传导和旁观者细胞的激活可能会引起毒性。 IL-23 是一种双亚基细胞因子，已知可促进记忆 T 细胞和 17 型辅助 T 细胞的增殖。我们发现，在 T 细胞抗原受体 (TCR) 刺激后，T 细胞上调 IL-23 受体和 IL-23α p19 亚基，但不上调 p40 亚基。我们改造了 T 细胞（p40-Td 细胞）中 p40 亚基的表达，并通过自分泌 IL-23 信号传导在激活的 T 细胞中获得了选择性增殖活性。与 CAR T 细胞相比，p40-Td CAR T 细胞在体外表现出更高的抗肿瘤能力，颗粒酶 B 增加，PD-1 表达减少。在两个异种移植和两个同基因实体瘤小鼠模型中，p40-Td CAR T 细胞与 CAR T 细胞相比显示出更优异的功效，并且与表达 IL-18 或 IL-15 的 CAR T 细胞相比副作用减弱。