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

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-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.

Th1 cytokines in conjunction with pharmacological Akt inhibition potentiate apoptosis of breast cancer cells in vitro and suppress tumor growth in vivo

“…Interestingly, post-vaccine recruitment of CD4 pos T cells into peritumoral areas strongly predominate over CD8 pos T cells, suggesting an effector mechanism dependent at least in part on Th cells. Consistent with this notion, we and others have found that paired Th1 cytokines IFN-γ and TNF-α induced senescence and/or apoptosis in vitro for a variety of cancer cell lines (both human and murine) [5][6][7]. We also showed that in many cases these cytokines could drive down the expression of HER family members on the surface of breast cancer cells [6].…”

Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

“…TP53 mutant cells are more sensitive to DNA damage (Brown and Wouters, 1999; Bunz et al, 1999), but cells that survive can undergo p53-independent senescence in culture (Chang et al, 1999b). Indeed, we found that in two TP53 mutant breast cancer cell lines shown to become senescent after chemotherapy, BT474 (Rosemblit et al, 2018) and T47D (Rastogi et al, 2006), cells that survived chemotherapy could engulf neighboring NT cells (Fig. 3, B and C).…”

Effect of Estrogen Receptor Status on Circulatory Immune and Metabolomics Profiles of HER2-Positive Breast Cancer Patients Enrolled for Neoadjuvant Targeted Chemotherapy

“…Although TNF-α can be found at BC tissue level, to date it is unknown whether the TNF-α surrounding the tumor is produced and released by cancer cells as an evasion strategy from the host immune response or whether it is secreted by cells of the immune system that infiltrate the tumor tissue. Recent evidences reported that HER2-overexpressing BC cells are susceptible to apoptosis induced in vitro by T helper 1 cytokines as TNF-α [46,47]. Through a complex regulatory network, after its receptor activation, TNF-α has been found to induce apoptosis or necrosis but also an opposite effect inducing cell growth, invasion or propagation of cancer cells [48,49].…”