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Myc Cooperates with Ras by Programming Inflammation and Immune Suppression.

Published version
Peer-reviewed

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Authors

Kortlever, Roderik M 
Sodir, Nicole M 
Wilson, Catherine H 
Burkhart, Deborah L 

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.

Description

Keywords

CCL9, IL-23, Myc, NK cells, Ras, immune suppression, inflammation, lung cancer, oncogene cooperation, tumor microenvironment, Adenocarcinoma, Adenoma, Animals, Carcinogenesis, Chemokines, CC, Disease Models, Animal, Female, Inflammation, Interleukin-23, Lung Neoplasms, Macrophage Inflammatory Proteins, Macrophages, Male, Mice, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

171

Publisher

Elsevier BV
Sponsorship
Cancer Research Uk (None)
Cancer Research Uk (None)
European Research Council (294851)
Cancer Research UK (19013)
Cancer Research UK (22585)