Abstract B086: Disease-critical macrophage populations interact with stroma to modulate the tumor microenvironment

Abstract Myeloid cells in the tumor microenvironment (TME) exhibit diverse functions, from pro-tumor to anti-tumor. To elucidate myeloid heterogeneity, we developed a deep-learning model to annotate 20 myeloid subtypes in single-cell data. We identified two macrophage populations, macro_SPP1 and macro_C1QC, which were pan-cancer, enriched in tumors compared to normal tissues, and linked to clinical outcomes. Higher macro_SPP1 abundance correlated with IO non-responders, pre-IO treatment, and lower inflammation, while macro_C1QC showed the opposite trends. We developed and validated gene signatures to quantify these macrophages in bulk RNAseq. Applying these signatures to TCGA and real-world data, we confirmed that macro_SPP1 was associated with worse survival and poor IO response, whereas macro_C1QC was linked to better outcomes. Tumors with chromosome 9p21 deletions had higher macro_SPP1 and fibroblast signatures, suggesting a TME influence on macrophage heterogeneity. Cell-cell communication analysis in single-cell data revealed that fibroblasts sent the strongest signals to macrophages in lung and pancreatic cancers. Fibroblast-derived ligands such as FN1 and collagens exhibited stronger signaling to macro_SPP1 than macro_C1QC, and colocalized with macro_SPP1 spatially. Conversely, macro_SPP1 sent higher total signals to other cells in the TME than macro_C1QC, with SPP1 to fibroblasts and endothelial cells being the most differentiating signal. In summary, we identified two disease-critical macrophage populations: pro-tumor macro_SPP1 and anti-tumor macro_C1QC. We found interactions between macrophages and fibroblasts as key modulators of the TME. Citation Format: Weiwei Zhong, Mitra Ansariola, Micaela Tatman, Rachel Wester, Kim Van Naarden Braun, Shameek Biswas. Disease-critical macrophage populations interact with stroma to modulate the tumor microenvironment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B086.