Myc Cooperates with Ras by Programming Inflammation and Immune Suppression

Summary

The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRas ^G12D -driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4 ⁺CD8 ⁺ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.

Graphical Abstract

Highlights

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  Myc and Ras cooperate in vivo through the tumor microenvironment

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  Myc directly programs angiogenesis, inflammation, and immune suppression

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  IL-23 and CCL9 are cell non-autonomous effectors of Myc-driven lung carcinogenesis

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  Myc-driven tumor growth and maintenance depend on immune suppression

Abstract

Oncogenic Myc activity orchestrates an immune suppressive tumor microenvironment.