Mutant p53 sensitizes KRAS-driven lung adenocarcinoma to immunotherapy by repressing SPP1.

Abstract

The efficacy of immune checkpoint blockade (ICB) in lung adenocarcinoma (LUAD) is limited by primary or acquired resistance, especially in genetically defined subsets. We investigated the impact of <i>KRAS/TP53</i> co-mutation on ICB response. Our analysis reveals that <i>KRAS/TP53</i> co-mutation is associated with favorable ICB outcomes, a phenotype orchestrated by secreted phosphoprotein 1 (SPP1). Mechanistically, mutant p53 and <i>KRAS</i> exert opposing effects on SPP1. Mutant p53 synergizes with transcription factor FOXA1 to repress <i>SPP1</i> transcription, whereas <i>KRAS</i> activates the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-signal transducer and activator of transcription 1 (STAT1) axis to up-regulate <i>SPP1</i>. Consequently, reduced SPP1 level in <i>KRAS/TP53</i> co-mutant LUAD impairs myeloid-derived suppressor cell (MDSC) recruitment and increases CD8+ T cell infiltration. Notably, SPP1 blockade synergizes with anti-programmed death-1 (PD-1) therapy to suppress tumor growth in <i>KRAS</i>-mutant xenograft models. Collectively, we delineate a mutant p53-FOXA1-SPP1 regulatory axis that modulates ICB susceptibility and unveil a synergistic combination therapy strategy.