Phosphatidylserine targeting antibody in combination with tumor radiation and immune checkpoint blockade promotes anti-tumor activity in mouse B16 melanoma

Abstract

Abstract Phosphatidylserine (PS) is a phospholipid that is exposed on surface of apoptotic cells, some tumor cells and tumor endothelium. It has been shown to promote immunosuppressive signals in the tumor microenvironment. Radiation therapy (RT) is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that RT induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in treated tumors. In this study, we show that irradiation of B16 melanoma causes an increase in PS expression on the surface of viable tumor and immune infiltrates. We subsequently examined the effects of combining RT with an antibody that targets PS (mch1N11) and immune checkpoint blockade (anti-PD-1) in B16 melanoma. We found that treatment with mch1N11 synergizes with RT to improve anti-tumor activity and overall survival in tumor bearing mice. In addition, the triple combination of mch1N11, RT and anti-PD-1 treatment displayed even greater anti-tumor and survival benefit. Analysis of immune responses in the tumors of treated animals revealed a shift towards a pro-inflammatory M1 phenotype after treatment with RT and mch1N11. In addition, analysis of the adaptive immune response revealed an increase in antigen-specific CD8 T cell infiltration in the tumors as well as increased activation, effector function and differentiation in the triple combination therapy. This finding highlights the potential of combining these agents to improve outcome in patients with advanced-stage cancer and may inform the design of future clinical trials.