Disabling of the erbB Pathway Followed by IFN-γ Modifies Phenotype and Enhances Genotoxic Eradication of Breast Tumors

Abstract

Summary Reversion of the malignant phenotype of erbB2-transformed cells can be driven by anti-erbB2/neu monoclonal antibodies (mAb), which disrupt the receptor's kinase activity. We examined the biologic effects of IFN-γ alone or after anti-erbB2/neu mAb treatment of erbB2-positive cells. IFN-γ had no effect on its own. Treatment of the tumors with anti-erbB2/neu mAb followed by IFN-γ led to dramatic inhibition of tumor growth in vitro and in vivo with minimal mAb dosing. Sequential therapy enhanced the effects of chemotherapy. Moreover, IFN-γ with mAb treatment of mice with IFNγR knock down tumors did not demonstrate marked synergistic eradication effects, indicating an unexpected role of IFN-γ on the tumor itself. Additionally, mAb and IFN-γ treatment also in duced immune host responses that enhanced tumor eradication. Biochemical analyses identified loss of Snail expression in tumor cells, reflecting diminution of tumor stem cell-like properties as a consequence of altered activity of GSK3-β and KLF molecules.

Assessment of expression of interferon γ (IFN-G) gene and its antisense (IFNG-AS1) in breast cancer

“…The existence of similar mechanism in breast cancer cells needs to be assessed. However, the direct effect of IFN-γ on HER2-positive breast cancer cells as reported by Nagai et al [ 11 ] supports a similar function in the context of breast cancer.…”

Enhanced Prevention of Breast Tumor Metastasis by Nanoparticle‐Delivered Vitamin E in Combination with Interferon‐Gamma

“…Interestingly, IFN‐γ‐defined beneficial outcomes are seldom reported when used alone, 6 as IFN‐γ upregulates PD‐L1 expression, causing the adaptive cancer immune resistance even though it can also activate anticancer immunity. In this study, PD‐L1 expression was well controlled by α‐TOS in IFN‐γ/NP‐TOS15 combination treatment, tumor growth was effectively inhibited, and tumor metastasis was magnificently prevented in the short observation period.…”

“…IFN‐γ facilitates anticancer immunity via recruiting highly immunogenic cells such as CD4 + and CD8 + T cells, and infiltrates M1 phase tumor associated macrophages (TAMs) 5. However, most clinical trials have failed in inhibiting cancer progression by IFN‐γ 6. The major reason is that long‐term exposure to IFN‐γ causes adaptive cancer immune resistance 3.…”

GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism

“…Nonetheless, the single-agent efficacy of IFNs is comparable to many currently used chemotherapeutics. A number of recent reports indicate that the success of conventional chemotherapeutics, targeted anti-cancer agents, radiotherapy and immunotherapy relies on type-I IFN signaling [9–14] in vivo . As a result, several human cancers accumulate IFN signaling defects to escape from growth suppression [15].…”