Spatial transcriptomics reveals heterogeneity of macrophages in the tumor microenvironment of granulomatous slack skin

Granulomatous slack skin (GSS) is an extremely rare subtype of cutaneous T-cell lymphoma accompanied by an abundant number of macrophages and is clinically characterized by the development of pendulous skin folds. However, the characteristics of these macrophages in GSS remain unclear. Here, we conducted a spatial transcriptomic study on one frozen GSS sample and drew transcriptomic maps of GSS for the first time. Gene expression analysis revealed the enrichment of three clusters with macrophage transcripts, each exhibiting distinct characteristics suggesting that their primary composition consists of different subpopulations of macrophages. The CD163⁺ /CD206⁺ cluster showed a tumor-associated macrophage (TAM) M2-like phenotype and highly expressed ZFP36, CCL2, TNFAIP6, and KLF2, which are known to be involved in T-cell interaction and tumor progression. The APOC1⁺ /APOE⁺ cluster presented a non-M1 or -M2 phenotype and may be related to lipid metabolism. The CD11c⁺ /LYZ⁺ cluster exhibited an M1-like phenotype. Notably, these cells strongly expressed MMP9, MMP12, CHI3L1, CHIT1, COL1A1, TIMP1, and SPP1, which are responsible for extracellular matrix (ECM) degradation and tissue remodeling. This may partially explain the symptoms of cutaneous relaxation in GSS. Further immunohistochemistry on four GSS cases demonstrated that CD11c predominantly marked granulomas and multinucleated giant cells, whereas CD163 was mainly expressed on scattered macrophages, appearing as a mutually exclusive pattern. The expression pattern of MMP9 overlapped with that of CD11c, implying that CD11c⁺ macrophages may be a source of MMP9. Our data shed light on the characteristics of macrophages in the GSS microenvironment and provide a theoretical basis for the application of MMP9 inhibitors to prevent cutaneous relaxation of GSS. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.