Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Oncology, Second Affiliated Hospital of Xi'an, Jiaotong University, Xi'an, China.
Nat Biotechnol. 2020 Apr;38(4):448-459. doi: 10.1038/s41587-019-0398-2. Epub 2020 Feb 3.
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.
细胞因子如白细胞介素（IL）-15 可刺激 T 细胞增殖，被探索用于增强嵌合抗原受体（CAR）T 细胞的抗肿瘤活性。然而，T 细胞中组成性细胞因子信号和旁观者细胞的激活可能导致毒性。IL-23 是一种二聚体细胞因子，已知可促进记忆 T 细胞和 T 辅助 17 细胞的增殖。我们发现，在 T 细胞抗原受体（TCR）刺激后，T 细胞上调了 IL-23 受体和 IL-23α p19 亚单位，但不上调 p40 亚单位。我们通过工程表达 T 细胞中的 p40 亚单位（p40-Td 细胞），并通过自分泌 IL-23 信号获得激活的 T 细胞的选择性增殖活性。与 CAR T 细胞相比，p40-Td CAR T 细胞在体外显示出更好的抗肿瘤能力，表现为颗粒酶 B 表达增加和 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，与 CAR T 细胞相比，p40-Td CAR T 细胞显示出更好的疗效，与表达 IL-18 或 IL-15 的 CAR T 细胞相比，减轻了副作用。
