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

Abstract

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 Pathological Society of Great Britain and Ireland.

Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis

“…Multinucleated osteoclasts depend on mitochondrial oxidative phosphorylation for their resorptive activity that remodels the bone matrix ( Jin et al, 2014 ; Lemma et al, 2016 ). Interestingly, Trem2 + LAMs expressing Spp1 showed a transcriptional profile similar to osteoclasts during advanced stages of murine atherosclerosis ( Cochain et al, 2018 ), and human multinucleated giant cells express MAM markers such as SPP1, MMP9, CHI3L1 in granulomatous slack skin ( Feng et al, 2023 ). Multinucleated adipose tissue macrophages, probably derived from SPP1-expressing LAMs, also show functional and morphological resemblance with osteoclasts ( Olona et al, 2021 ).…”

Spatial cell graph analysis reveals skin tissue organization characteristic for cutaneous T cell lymphoma

“…While several studies have explored the spatial heterogeneity of tumor microenvironment in CTCL and its potential relevance in prognosis 10,11 , a systematic quantification of spatial tissue heterogeneity in the context of CTCL does not exist. This prompted us to generate imaging-based spatially resolved protein abundance maps of skin tissue samples from CTCL, AD, and PSO patients treated at the University Hospital Erlangen, using multi-epitope ligand cartography (MELC) 12,13 .…”