MYC Induces Immune Suppression to Promote Lung Tumorigenesis

The KRAS and MYC oncogenes cooperate to drive tumorigenesis, and KRAS mutations and MYC overexpression occur frequently in patients with non–small cell lung cancer. However, the mechanisms underlying their cooperation have not been elucidated. Kortlever and colleagues used a mouse model of KRAS^G12D-driven lung cancer with inducible and reversible MYC expression to understand the contribution of MYC in KRAS-driven tumorigenesis. Induction of MYC expression in lung epithelial cells accelerated KRAS^G12D-driven lung tumorigenesis, but MYC expression did not affect the lung phenotype in the absence of KRAS^G12D. Tumors driven by MYC and KRAS^G12D were more aggressive, exhibiting enhanced proliferation, invasion, inflammation, and angiogenesis compared with tumors driven by KRAS^G12D alone. MYC induced rapid widespread changes to the tumor stroma, including an influx of CD206⁺ macrophages, a loss of CD3⁺ T cells and B220⁺ B cells, a reduction in natural killer (NK) cells, and the onset of angiogenesis. These MYC-driven stromal changes were mediated by induction of the MYC effectors CCL9 and IL23, and blockade of CCL9 and IL23 suppressed the MYC-driven effects and induced apoptosis, resulting in a reduction in tumor burden in vivo. Tumors driven by MYC and KRAS^G12D rapidly became dependent upon MYC expression, as removal of MYC expression resulted in decreased tumor cell proliferation, an efflux of macrophages, normalization of the vasculature, and an influx of T cells and NK cells. The tumor regression induced by MYC loss was NK cell–dependent and independent of CD4⁺ and CD8⁺ T cells, but MYC deactivation did not lead to a complete tumor regression. In addition to elucidating a mechanism by which MYC cooperates with KRAS^G12D to promote lung tumorigenesis, these findings reveal a role for MYC in programming an immunosuppressive tumor microenvironment.

Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Brown Swigart L, et al. Myc cooperates with Ras by programming inflammation and immune suppression. Cell 2017;171:1301–15.

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