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.
Highlights
The human epidermal growth factor receptor family is comprised of four known members (HER-1-4)
In follow-on retrospective studies, patients who had invasive HER-2pos breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab [18]
When HER-2 Th1 immunity was compared in the pCR versus non-pCR group, it was found that higher retained Th1 immunity was independently associated with pCR [18]
Summary
The human epidermal growth factor receptor family is comprised of four known members (HER-1-4). They each perform a variety of normal physiological functions, but can serve as oncodrivers in tumorigenesis [1, 2]. HER-2 has no known ligand, while HER-3 lacks kinase activity; but as a heterodimer, they form a highly efficient functional unit that constitutes the most active signaling dimer in this family [3]. HER-2 overexpression in breast cancers is associated with invasiveness, poor prognosis and resistance to chemotherapy [4, 5]. HER-2 and HER-3 are attractive targets for novel breast cancer treatments, both pharmacological and immunological
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