[PDF][PDF] Myc cooperates with Ras by programming inflammation and immune suppression

RM Kortlever, NM Sodir, CH Wilson, DL Burkhart… - Cell, 2017 - cell.com
RM Kortlever, NM Sodir, CH Wilson, DL Burkhart, L Pellegrinet, LB Swigart, TD Littlewood…
Cell, 2017cell.com
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 …
Summary
The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-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.
cell.com