cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas

We discovered that KRAS-mutant lung adenocarcinomas (LADC) co-opt CREB in order to evade the innate immune system: KRAS-driven CREB activation in LADC suppresses the expression of CXCR1 ligands that would otherwise recruit neutrophils to the tumor site. CREB was overexpressed in murine KRAS-mutant LADC, pulmonary Creb1-deletion inhibited disease development, and Creb1-overexpression boosted the tumorigenicity of KRAS-mutant cells. Conditional Creb1 deletion in Kras-mutant LADC cells caused overexpression of CXCR1/2 ligands, and lung tumor-bearing Creb1-deleted mice displayed increased pulmonary neutrophils. Cxcr1-deficient mice were selectively permissive to KRAS-mutant tumor growth and showed defective neutrophil recruitment. The pro-tumor effects of CREB required intact host-Cxcr1 and those of host-Cxcr1 necessitated mutant KRAS in cancer cells. Pharmacologic CREB blockade prevented tumor growth and restored neutrophil recruitment only when initiated before immune evasion of KRAS-mutant LADC cells. CREB and CXCR1 expression were respectively restricted to tumor and stromal cells of human LADC, while CREB-controlled genes profoundly impacted survival. In summary, CREB-mediated immune evasion of KRAS-mutant LADC rests on signaling to myeloid CXCR1 and is actionable. Compare differential gene expression between murine urethane-induced lung adenocarcinoma cells expressing or silenced for Creb1