Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.
Cell
; 171(6): 1301-1315.e14, 2017 Nov 30.
Article
in En
| MEDLINE
| ID: mdl-29195074
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Adenocarcinoma
/
Adenoma
/
Proto-Oncogene Proteins p21(ras)
/
Proto-Oncogene Proteins c-myc
/
Lung Neoplasms
Limits:
Animals
Language:
En
Journal:
Cell
Year:
2017
Document type:
Article
Affiliation country: