Synergistic effect of IFN-γ on breast cancer targeted therapy

Abstract

Abstract ErbB2 is amplified in ~30% of breast cancer patients, and its amplification is associated with poor prognosis and worse survival outcome. We examined the synergistic effect of interferon-γ (IFN-γ) with anti-erbB2/neu mAb on erbB2-positive cancer model. IFN-γ showed marginal effects on its own, indicating that immune therapies mediated by this cytokine alone are unlikely to be beneficial. However, we discovered that treatment of the tumors with anti-erbB2/neu mAb concomitant with IFN-γ led to dramatic inhibition of in vivo tumor growth in the syngeneic tumor model and the preventional MMTV-neu transgenic mouse tumor model. We noted an increase of M1 macrophage accumulation in the tumor tissues as well as diminished myeloid derived suppressor cells, and increased CD8+ T cell cytotoxicity against tumor cells in the IFN-γ plus anti-erbB2/neu mAb treated mice. The tumor cells treated with both mAb and IFN-γ underwent changes in tumor stem cell marker ALDH-1, indicating a loss of stem cell-like properties, while mAb treatment alone did not accomplish this phenotypic change. We found that IFN-γ treatment significantly increase tumor PD-L1 expression, so we included anti-PD-1 or PD-L1 antibody with this combination therapy. Interestingly, anti-PD-L1 antibody further reduced tumor growth, while anti-PD-1 did not affect very much. These results indicate that the treatment of IFN-γ can improve targeted therapy, and further induce PD-L1 expression on tumor cells, creating a new target on the tumor cells for anti-PD-L1 therapy.