美国北卡罗莱纳大学教堂山分校Yang Xu和Gianpietro Dotti研究组合作发现：在实体瘤中，工程化改造的白介素（IL）-23改善了嵌合抗原受体（CAR） T细胞的功能。该研究2020年2月3日在线发表在国际学术期刊《自然—生物技术》上。

研究人员发现，在T细胞抗原受体（TCR）刺激下，T细胞上调IL-23受体和IL-23αp19亚基，而非p40亚基的表达。在T细胞（p40-Td细胞）中，研究人员工程化表达了p40亚基，并通过自分泌IL-23信号通路在活化T细胞中获得了选择增殖活性。体外实验表明，与CAR T细胞相比，p40-Td CAR T细胞显示出改善的抗肿瘤能力、颗粒酶B增加而PD-1表达减少。在两个异种移植和两个同系实体瘤小鼠模型中，与表达IL-18或IL-15的CAR T细胞相比，p40-Td CAR T细胞具有比CAR T细胞更优越的功效，并具有低副作用。

据了解，利用细胞因子刺激T细胞增殖，例如白介素（IL）-15，已被作为增强CART细胞抗肿瘤活性的手段。但是，T细胞中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是一个两亚基的细胞因子，能促进记忆T细胞和辅助型T细胞17的增殖。

附：英文原文

Title: Interleukin-23 engineering improves CAR T cell function in solid tumors

Author: Xingcong Ma, Peishun Shou, Christof Smith, Yuhui Chen, Hongwei Du, Chuang Sun, Nancy Porterfield Kren, Daniel Michaud, Sarah Ahn, Benjamin Vincent, Barbara Savoldo, Yuliya Pylayeva-Gupta, Shuqun Zhang, Gianpietro Dotti, Yang Xu

Issue&Volume: 2020-02-03

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.

DOI: 10.1038/s41587-019-0398-2

Source: https://www.nature.com/articles/s41587-019-0398-2