The Synergistic Antitumor Effect of Combined Anti-Human Epidermal Growth Factor Receptor 2 Antibody and Gamma Interferon Therapy on Antibody-resistant Breast Cancer Cells

Abstract

The anti-human epidermal growth factor receptor 2 (HER2) antibody (Ab) is a molecularly targeted Ab for cancer therapy. In the eld of breast cancer, approximately 20% overexpress HER2 protein. However, the recurrence rate is 30% and the metastasis rate is 18% one year after treatment of anti-HER2 Ab for HER2 positive breast cancer. The resistance to Ab treatment is a major problem for patients. We previously reported that anti-HER2 Ab and Gamma Interferon (IFN-γ) combined therapy show a higher anti-tumor effect than typical therapy in in vitro and in vivo mouse experiments. In this study, we evaluated whether anti-HER2 Ab and IFN-γ combined therapy shows a good synergistic effect against drug-resistant HER2 positive breast cancer cells and a higher antitumor effect than chemotherapy as a conventional clinical treatment. Further, we evaluated a synergy effect with the PD-L1 as a new check point inhibitor. The resistant cell lines were made under the continuous presence of Ab until cell growth was not affected by the drug. The resistant cells were divided into the appropriate number of groups, and then treated with anti-cancer therapy. We evaluated the antitumor effect for both the in vitro study and in vivo mouse xenograft model prepared with the same immunogenicity. The differences of immuno uorescence staining of CD8, Gr-1 and PDL-1 in tissues were investigated, especially in relation to the immune system. The combined therapy showed a signi cantly higher antitumor effect than other groups in in vitro and in vivo experiments. The combined therapy affected anti-tumor immunity in this immunofluorescence experiment. Taken together, we showed the possibility that combined therapy could be an effective treatment option for anti-HER2 Ab resistant breast cancer, thus helping patients suffering from cancer progression after developing treatment resistance.