Immune-evasion of KRAS-mutant lung adenocarcinoma mediated by cAMP response element-binding protein
Giotopoulou, G. A.; Ntaliarda, G.; Marazioti, A.; Lilis, I.; Kalogianni, F.; Tourkochristou, E.; Spiropoulou, N.; Giopanou, I.; Spella, M.; Iliopoulou, M.; Korfiati, A.; Mantamadiotis, T.; Rosero, C.; Goldmann, T.; Marwitz, S.; Stathopoulos, G. T.
Show abstract
cAMP response element-binding protein (CREB) mediates proliferative and inflammatory gene transcription in neurodegeneration and cancer, but its role in malignant immune-evasion of lung adenocarcinoma (LUAD) is unknown. We show that human LUAD of smokers are frequently altered along the CREB pathway and we employ mouse models to discover that KRAS-mutant LUAD co- opt CREB to evade immune rejection by tumoricidal neutrophils. For this, KRAS- driven CREB activation suppresses CXC-chemokine expression and prevents recruitment of CXCR1+ neutrophils. CREB1 is shown to be pro-tumorigenic in five different LUAD models, a function that is dependent on host CXCR1. Pharmacologic CREB blockade prevents tumor growth and restores neutrophil recruitment only when initiated before immune-evasion of KRAS-mutant LUAD. CREB and CXCR1 expression in human LUAD are compartmentalized to tumor and stromal cells, respectively, while CREB-regulated genes and neutrophils impact survival. In summary, CREB-mediated immune evasion of KRAS-mutant LUAD relies on signaling to neutrophil CXCR1 and is actionable.
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