| First Author | Kortlever RM | Year | 2017 |
| Journal | Cell | Volume | 171 |
| Issue | 6 | Pages | 1301-1315.e14 |
| PubMed ID | 29195074 | Mgi Jnum | J:251862 |
| Mgi Id | MGI:6101027 | Doi | 10.1016/j.cell.2017.11.013 |
| Citation | Kortlever RM, et al. (2017) Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell 171(6):1301-1315.e14 |
| abstractText | 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. |
