Genotype-Specific Macrophage Programs in the NSCLC Microenvironment

Analysis of virtual macrophage revealed a diversity of transcriptional programs acquired from interacting with tumor cells or fibroblasts neighborhoods. A subset of these programs were associated with macrophage polarization towards immunosuppressive SPP1+ or immunogenic CXCL9+ states, known to correlate with patients‘ response to immunotherapy. We further identified programs in tumor cells and fibroblasts that correlate with these macrophage states. Specifically, our experiments unveiled collagen expressing fibroblasts promoting SPP1+ virtual macrophage phenotypes. This population of fibroblasts was enriched in KRAS STK11 mutant vs KRAS mutant tumors, suggesting genotype specific TME characteristics that may account for resistance to immune checkpoint therapy in KRAS STK11 mutant tumors. Our spatial virtual cell foundation model approach uncovers novel multicellular processes within the NSCLC TME, and helps elucidate how spatially-resolved events shape macrophage polarization. This approach identifies actionable targets, offering new insights to enhance immunotherapy efficacy and reverse immunosuppressive tumor environments.

Read more