A cellular and spatial atlas ofTP53-associated tissue remodeling in lung adenocarcinoma

Abstract

AbstractTP53is the most frequently mutated gene across many cancers and is associated with shorter survival in non-small cell lung cancer (NSCLC). To understand howTP53-mutant (TP53mut) malignant cells interact with the tumor microenvironment (TME) at a molecular, cellular, and tissue level, we built a multi-omic cellular and spatial tumor atlas of 23 treatment-naïve NSCLC human tumors. We identified significant differences in malignant expression programs and spatial cell-cell interactions betweenTP53mutandTP53WTtumors and found that highly-entropicTP53mutmalignant cells lose alveolar identity and coincide with an increased abundance of exhausted T cells and immune checkpoint interactions with implications for response to checkpoint blockade. We also identified a multicellular, pro-metastatic, hypoxic tumor niche, where highly-plastic,TP53mutmalignant cells expressing epithelial to mesenchymal transition (EMT) programs associate withSPP1+myeloid cells and collagen-expressing cancer-associated fibroblasts. Our approach can be further applied to investigate mutation-specific TME changes in other solid tumors.