期刊
CELL
卷 171, 期 6, 页码 1301-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.11.013
关键词
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资金
- NWO-Rubicon from the Netherlands Organisation for Scientific Research [825.08.022]
- Cancer Research UK [C4750/A12077, C4750/A19013]
- European Research Council [294851]
- SU2C/CR UK/Lustgarten/CR UK/Lustgarten Transatlantic Pancreatic Cancer Dream Team [C4750/A22585]
- NIH/NCI [2RO1 CA98018]
- Cancer Research UK [12077, 22585, 19013] Funding Source: researchfish
- European Research Council (ERC) [294851] Funding Source: European Research Council (ERC)
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 immunesuppressed 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.
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