T cell

Immune system

CD28

Cancer research

Biochemistry

Biology

Cancer

Cytotoxic T cell

In vitro

Immunology

Genetics

Nature

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&nbsp;and&nbsp;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. A trispecific antibody targeting HER2 and T cells&nbsp;stimulates CD4 T cell-dependent inhibition of of breast cancer&nbsp;cell proliferation in vitro and tumor&nbsp;regression&nbsp;in a humanized mouse model.

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