T-helper 1-type cytokines induce apoptosis and loss of HER-family oncodriver expression in murine and human breast cancer cells

Abstract

// Prachi Namjoshi 1 , Lori Showalter 1 , Brian J. Czerniecki 2 and Gary K. Koski 1 1 Department of Biological Sciences, Kent State University, Kent, Ohio, USA 2 Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence to: Gary K. Koski, email: dendritic_cell@hotmail.com Keywords: apoptosis; HER-2; T-helper 1; IFN-γ; TNF-α Received: February 16, 2016     Accepted: May 12, 2016     Published: October 15, 2019 ABSTRACT A recent neoadjuvant vaccine trial for early breast cancer induced strong Th1 immunity against the HER-2 oncodriver, complete pathologic responses in 18% of subjects, and for many individuals, dramatically reduced HER-2 expression on residual disease. To explain these observations, we investigated actions of Th1 cytokines (TNF-α and IFN-γ) on murine and human breast cancer cell lines that varied in the surface expression of HER-family receptor tyrosine kinases. Breast cancer lines were broadly sensitive to the combination of IFN-γ and TNF-α, as evidenced by lower metabolic activity, lower proliferation, and enhanced apoptosis, and in some cases a reversible inhibition of surface expression of HER proteins. Apoptosis was accompanied by caspase-3 activation. Furthermore, the pharmacologic caspase-3 activator PAC-1 mimicked both the killing effects and HER-2-suppressive activities of Th1 cytokines, while a caspase 3/7 inhibitor could prevent cytokine-induced HER-2 loss. These studies demonstrate that many in vivo effects of vaccination (apparent tumor cell death and loss of HER-2 expression) could be replicated in vitro using only the principle Th1 cytokines. These results are consistent with the notion that IFN-γ and TNF-α work in concert to mediate many biological effects of therapeutic vaccination through the induction of a caspase 3-associated cellular death mechanism.