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

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 therapies2-4. 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.

• Authors: Edward Seung, Zhen Xing, Lan Wu, Ercole Rao, Virna Cortez-Retamozo, Beatriz Ospina, Liqing Chen, Christian Beil, Zhili Song, Bailin Zhang, Mikhail Levit, Gejing Deng, Andrew Hebert, Patrick Kirby, Aiqun Li, Emma-Jane Poulton, Rita Vicente, Audrey Garrigou, Peter Piepenhagen, Greg Ulinski, Michele Sanicola-Nadel, Dinesh S Bangari, Huawei Qiu, Lily Pao, Dmitri Wiederschain, Ronnie Wei, Zhi-Yong Yang, Gary J Nabel
• Journal: Nature (Nature) Vol. 603 Issue 7900 Pg. 328-334 (Mar 2022) ISSN: 1476-4687 [Electronic] England
• PMID: 35197632 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• CD28 Antigens
• ERBB2 protein, human
• Erbb2 protein, mouse
• Receptor, ErbB-2

Topics

• Animals
• Breast Neoplasms (drug therapy, metabolism)
• CD28 Antigens (metabolism)
• CD4-Positive T-Lymphocytes
• CD8-Positive T-Lymphocytes
• Female
• Humans
• Mice
• Receptor, ErbB-2 (genetics)