Myc Cooperates with Ras by Programming Inflammation and Immune Suppression
Open accessAbstract
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.
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SHP099 and G12C-I each decreased the expression of chemokine/cytokine genes that favor immune-suppressive CD11b+ myeloid cells (e.g., CXCL1-5; CCL9).
“while decreasing the expression of those that favor immune-suppressive CD11b+ myeloid cells (e.g., CXCL1-5; CCL9; Chow and Luster, 2014; Kortlever et al., 2017; Liao et al., 2019; Nagarsheth et al., 2017; Fig. 5, I and J).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Kortlever et al., 2017
LKB1 inactivation also affects non-immune parts of the KrasG12D mouse tumor microenvironment, raising collagen deposition via higher LOX expression and altering angiogenesis.
“LKB1 inactivation has also been reported to impinge on non-immune components of the microenvironment of KrasG12D-mutant mouse tumors, including increased collagen deposition as a result of elevated lysyl oxidase (LOX) expression and effects on angiogenesis139, 140.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [139]
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References 83 · Cited by 553
- Authors
- Kortlever, R. M., Sodir, N. M., Wilson, C. H., Burkhart, D. L., Pellegrinet, L., Brown Swigart, L., Littlewood, T. D., & Evan, G. I.
- Affiliations
- University of California, San Francisco (US)
- University of Cambridge (GB)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 171
- Issue
- 6
- Pages
- 1301-1315.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5720393
- OpenAlex
- W2774267942
- Cited by
- 553
- References
- 83
- Citations by year
- 2026: 47 · 2025: 55 · 2024: 77 · 2023: 73 · 2022: 67 · 2021: 80 · 2020: 68 · 2019: 52 · 2018: 33 · 2017: 1
- FWCI
- 19.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Netherlands Organisation for Scientific Research (825.08.022)
- Cancer Research UK (C4750/A12077, C4750/A19013)
- NIH/NCI (2RO1 CA98018)
- European Research Council (294851)
- SU2C/CR UK/Lustgarten
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- c-Myc, KRAS G12D, oncogene cooperation, lung adenocarcinoma, inflammation, immunosuppression, CCL9, IL-23, macrophage recruitment, angiogenesis, PD-L1, T-cell exclusion, natural killer cells, tumor regression, tumor progression
- MeSH terms
- Adenocarcinoma, Adenoma, Animals, Disease Models, Animal, Female, Inflammation, Lung Neoplasms, Macrophages, Male, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Macrophage Inflammatory Proteins, Chemokines, CC, Mice, Interleukin-23, Tumor Microenvironment, Carcinogenesis
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