Oncodriver inhibition and CD4+ Th1 cytokines cooperate through Stat1 activation to induce tumor senescence and apoptosis in HER2+ and triple negative breast cancer: Implications for combining immune and targeted therapies

Cinthia Rosemblit, Jashodeep Datta, Lea Lowenfeld, Shuwen Xu, Amrita Basu, Krithika Kodumudi, Doris Wiener, Brian J. Czerniecki

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

In patients with HER2-expressing breast cancer many develop resistance to HER2 targeted therapies. We show that high and intermediate HER2-expressing cancer cell lines are driven toward apoptosis and tumor senescence when treated with either CD4+ Th1 cells, or Th1 cytokines TNF-α and IFN-γ, in a dose dependent manner. Depletion of HER2 activity by either siRNA or trastuzumab and pertuzumab, and subsequent treatment with either anti-HER2 Th1 cells or TNF-α and IFN-γ resulted in synergistic increased tumor senescence and apoptosis in cells both sensitive and cells resistant to trastuzumab which was inhibited by neutralizing anti-TNF-a and IFN-y. Th1 cytokines induced minimal senescence or apoptosis in triple negative breast cancer cells (TNBC); however, inhibition of EGFR in combination with Th1 cytokines sensitized those cells causing both senescence and apoptosis. TNF-α and IFN-γ led to increased Stat1 phosphorylation through serine and tyrosine sites and a compensatory reduction in Stat3 activation. Single agent IFN-y enhanced Stat1 phosphorylation on tyrosine 701 and similar effects were observed in combination with TNF-α and EGFR inhibition. These results demonstrate Th1 cytokines and antioncodriver blockade cooperate in causing tumor senescence and apoptosis in TNBC and HER2-expressing breast cancer, suggesting these combinations could be explored as non-cross-reactive therapy preventing recurrence in breast cancer.

Original languageEnglish (US)
Pages (from-to)23058-23077
Number of pages20
JournalOncotarget
Volume9
Issue number33
DOIs
StatePublished - May 1 2018
Externally publishedYes

Keywords

  • Breast cancer
  • CD4 T-helper immunity
  • HER2/neu
  • Triple negative

ASJC Scopus subject areas

  • Oncology

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