Research Papers:

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 and Brian J. Czerniecki _

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Oncotarget. 2018; 9:23058-23077. https://doi.org/10.18632/oncotarget.25208

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Cinthia Rosemblit1,2, Jashodeep Datta1, Lea Lowenfeld1, Shuwen Xu1, Amrita Basu2, Krithika Kodumudi2, Doris Wiener2 and Brian J. Czerniecki1,2

1Harrison Department of Surgical Research, Department of Surgery, University Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

2Department of Clinical Science, H Lee Moffitt Cancer Center, Tampa, FL, USA

Correspondence to:

Brian J. Czerniecki, email: [email protected]

Keywords: CD4+ T-helper immunity; HER2/neu; triple negative; breast cancer

Received: June 20, 2016     Accepted: April 02, 2018     Published: May 01, 2018


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-α and IFN-γ. 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-γ 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 anti-oncodriver 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.

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