CXCL9:SPP1 Macrophage Polarity Is Linked to Clinical Outcome in Cancer

The tumor microenvironment (TME) is comprised of a rich array of cell types that can have pro- or antitumor phenotypes. Single-cell RNA sequencing (scRNA-seq) is widely used to study tumor-associated stromal and immune cells, but most scRNA-seq approaches analyze cells from individual tumors together, thus failing to consider variation between patients. In this study, Bill, Wirapati, and colleagues developed an approach to study tumor-to-tumor variation in order to better understand TME composition and its relationship to clinical disease outcome. Analysis of an scRNA-seq dataset from patients with head and neck squamous cell carcinoma (HNSCC) revealed conserved stromal and immune cell signatures that correlated with disease progression, with the tumor-associated macrophage (TAM) gene signature demonstrating a particularly strong prognostic effect. The ratio of two genes, CXCL9 and SPP1, primarily drove this phenotype, and CXCL9 and SPP1 expression in macrophages was found to be mutually exclusive, poorly corresponded to established M1 and M2 signatures, and correlated with survival, with patients with SPP1^hi TAMs having worse clinical outcomes than those with CXCL9^hi TAMs. CXCL9- and SPP1-expressing (CS) TAM polarity also correlated with both immune cell infiltration and global gene expression profiles in other cell types in which specifically, CXCL9^hi TAM-associated genes were enriched for immune-related and inflammatory signatures, while SPP1^hi TAM-associated genes were enriched for epithelial–mesenchymal transition and hypoxia signatures. Moreover, spatial analyses revealed that TAMs accumulate in clusters of SPP1^hi or CXCL9^hi cells and reside in distinct TME niches. Furthermore, exogenous IFNγ administered to cell lines or dissociated human biopsies was sufficient to induce CXCL9 expression, while hypoxic conditions led to SPP1 induction, indicating that extrinsic TME factors can regulate CS TAM polarization. Importantly, CS polarization was also associated with overall survival in a wide variety of other cancer types, and analysis of additional HNSCC, non–small cell lung cancer, and colorectal cancer scRNA-seq datasets revealed similar CS TAM polarization and associated phenotypes. In summary, this study utilized tumor-to-tumor covariation to define a novel CS TAM polarity axis that controls many aspects of clinical response.

Bill R, Wirapati P, Messemaker M, Roh W, Zitti B, Duval F, et al. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science 2023;381:515–24.

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