Abstract 1698: Loss of MHC-I expression is associated with altered immune microenvironment and decreased response to PD-1 checkpoint inhibition

Abstract

Abstract Cancer immunotherapies, such as PD-1 inhibitors, achieve durable responses in a subset of cancer patients, however, a significant proportion of patients fail to respond to treatment. Defects in antigen presentation, such as the loss of MHC-I expression, are a major mechanism of resistance to PD-1 inhibitors. Developing new therapeutic strategies that overcome the lack of antigen presentation will improve cancer treatment and patient survival. To develop a pre-clinical model to evaluate therapies that could overcome resistance, we have generated a unique PD-1 blockade sensitive, syngeneic immunocompetent melanoma mouse model. We generated defects in antigen presentation using the CRISPR/Cas9 system, creating B2m-deficient melanoma cell lines. We demonstrated that B2m is necessary for IFN-gamma induced MHC-I surface expression. Unlike control tumors, we found that B2m-deficient tumors were resistant to PD-1 blockade, leading to decreased mouse overall survival. Using multi-parameter flow cytometry, we showed an increase in NK cell, regulatory T cell and dendritic cell infiltration in B2m-deficient tumors compared to controls, while the other immune cell population were unchanged. Since NK cell activity is negatively regulated by MHC-I, our findings suggest that additional factors are required to further invigorate infiltrating NK cells and to trigger a NK cell-mediated anti-tumor response. We are currently evaluating new approaches targeting NK cells and regulatory T cells on B2m-deficient tumors. This pre-clinical model could enable the development of a therapeutic strategy serving to improve the treatment of tumors lacking antigen presentation. Citation Format: Cecile Gstalder, Priya Pancholi, Dorota Sadowicz, Rizwan Haq. Loss of MHC-I expression is associated with altered immune microenvironment and decreased response to PD-1 checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1698.