High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis

Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (M4)) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two M4) markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory mono-cyte-derived M4) (MoM4)) expressing the monocytic marker SER-PINB2, and a more differentiated population, tumor-associated M4) (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2 thorn MoM4) had an early inflammatory profile, whereas GPNMB thorn TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2 thorn cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB thorn cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell-cell interaction analysis defined opposing roles for MoM4) and TAMs, suggesting that SERPINB2 thorn and GPNMB thorn cells are discrete populations of M4) and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can iden-tify nonredundant, clinically relevant markers for further transla-tion to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set M4) in an immunosuppres-sive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of M4) populations.

Automated summary

Two M4 markers associated with opposite clinical relevance were identified through single-cell analysis, indicating the importance of improved classification and prognostic classifiers for patients with colorectal liver metastasis.