美国赛诺菲研发Gary J. Nabel、Zhi-yong Yang和Lily Pao合作发现靶向 HER2 和 T 细胞的三特异性抗体通过 CD4 细胞抑制乳腺癌的生长。2022年2月23日出版的《自然》杂志发表了这项成果。

他们证明了靶向HER2、CD3 和 CD28 的三特异性抗体通过涉及CD4 依赖性抑制肿瘤细胞周期进程的机制在人源化小鼠模型中刺激乳腺癌的消退。尽管 CD8 T 细胞在体外直接介导肿瘤溶解，但 CD4 T 细胞通过在 G1/S 阻断癌细胞周期进程发挥抗增殖作用。此外，当 T 细胞亚群过继转移到人源化乳腺癌肿瘤小鼠模型中时，CD4 T 细胞单独抑制体内 HER2+ 乳腺癌的生长。RNA 微阵列分析显示，CD4 T 细胞显著降低了肿瘤细胞周期进程和增殖，同时也增加了促炎信号通路。总的来说，靶向HER2 的三特异性抗体通过直接抗肿瘤和由 CD4 T 细胞驱动的间接促炎/免疫效应诱导 T 细胞依赖性肿瘤消退。

据介绍，有效的抗肿瘤免疫取决于有效的 T 细胞对恶性肿瘤的反应的协调。免疫检查点抑制剂、T 细胞接合剂或嵌合抗原受体 T 细胞疗法已诱导人类癌症的消退。尽管 CD8 T 细胞作为这些反应的关键效应器发挥作用，但 CD4 T 细胞在其辅助功能之外的作用尚未确定。

附：英文原文

Title: A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells

Author: Seung, Edward, Xing, Zhen, Wu, Lan, Rao, Ercole, Cortez-Retamozo, Virna, Ospina, Beatriz, Chen, Liqing, Beil, Christian, Song, Zhili, Zhang, Bailin, Levit, Mikhail, Deng, Gejing, Hebert, Andrew, Kirby, Patrick, Li, Aiqun, Poulton, Emma-Jane, Vicente, Rita, Garrigou, Audrey, Piepenhagen, Peter, Ulinski, Greg, Sanicola-Nadel, Michele, Bangari, Dinesh S., Qiu, Huawei, Pao, Lily, Wiederschain, Dmitri, Wei, Ronnie, Yang, Zhi-yong, Nabel, Gary J.

Issue&Volume: 2022-02-23

Abstract: Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies1. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies2,3,4. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

DOI: 10.1038/s41586-022-04439-0

Source: https://www.nature.com/articles/s41586-022-04439-0