Abstract 535: Deregulated Myc is an immunosuppressive switch

Early tumor evolution through sustained oncogene activity selectively bypasses the engagement of cell-intrinsic tumor-suppressor signaling and cell-extrinsic microenvironmental restrictions. How the immune system may be involved is virtually unknown. We describe here the contributions of a conditional and reversible low-level expression of Myc in a mouse model of KrasG12D-driven non-small cell lung cancer. Deregulated Myc activity results in highly expansive tumors that appear embedded in inflamed regions and leads to a rapid reduction of mouse survival. Myc activation imposes an immediate switch to an immunosuppressive and pro-angiogenic microenvironment, facilitated through IL23- and CCL9-associated recruitment of PD-L1 loaded macrophages and local exclusion of T-lymphocytes. Reversibly, blocking the activity of Myc-driven IL23 and CCL9 expression or withdrawal of deregulated Myc activity in tumors established by oncogene cooperation results in tumor cell death and regression, associated with a collapse of the established microenvironmental changes and re-engagement of cytotoxic T-cells. During oncogene cooperation with Ras, deregulated Myc directs a sufficient and necessary switch to a microenvironment that shields tumor growth and expansion from immune suppression. Citation Format: Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Lamorna Swigart, Trevor D. Littlewood, Gerard I. Evan. Deregulated Myc is an immunosuppressive switch. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 535.