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Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer [spatial_ATAC]

ABSTRACT: The rising incidence of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), particularly among immunosuppressed individuals, underscores the need for a deeper understanding of the tumor microenvironment (TME) to develop effective and safe immunotherapies. This study employed single-cell multi-omic analyses to investigate the spatial distribution and transcriptional profiles of immune cells in NMSC from both immunocompetent and immunosuppressed patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. Instead, we identified a critical deficiency in antigen presentation by macrophages, leading to impaired T-cell diversity and clonal expansion. Additionally, a spatial epigenomic atlas of the NMSC TME revealed distinct spatial niches and epigenetic programs associated with immunosuppression. These findings highlight the central role of innate immunity in shaping anti-tumor responses and offer potential therapeutic targets to enhance immunotherapy in this vulnerable patient population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306129 | GEO | 2026/08/07

REPOSITORIES: GEO

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Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer

Project description:The rising incidence of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), particularly among immunosuppressed individuals, underscores the need for a deeper understanding of the tumor microenvironment (TME) to develop effective and safe immunotherapies. This study employed single-cell multi-omic analyses to investigate the spatial distribution and transcriptional profiles of immune cells in NMSC from both immunocompetent and immunosuppressed patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. Instead, we identified a critical deficiency in antigen presentation by macrophages, leading to impaired T-cell diversity and clonal expansion. Additionally, a spatial epigenomic atlas of the NMSC TME revealed distinct spatial niches and epigenetic programs associated with immunosuppression. These findings highlight the central role of innate immunity in shaping anti-tumor responses and offer potential therapeutic targets to enhance immunotherapy in this vulnerable patient population.

2026-08-07 | GSE308361 | GEO

Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer [Xenium Spatial Transcriptomics]

2026-08-07 | GSE306130 | GEO

Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer

Project description:The rising incidence of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), particularly among immunosuppressed individuals, underscores the need for a deeper understanding of the tumor microenvironment (TME) to develop effective and safe immunotherapies. This study employed single-cell multi-omic analyses to investigate the spatial distribution and transcriptional profiles of immune cells in NMSC from both immunocompetent (IC) and immunosuppressed (IS) patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. We found that IS tumors retain all requisite immune cell populations but display functional suppression and disrupted spatial organization. Our data revealed a limited number of distinct programs, particularly in macrophages and their spatially organized niches, that are linked to restricted T-cell repertoire diversity and impaired clonal expansion, providing a mechanistic bridge between innate dysfunction and adaptive immune failure. These perturbations were further confirmed by a novel spatial epigenomic atlas of the NMSC TME that revealed immune status–specific regulatory programs, including MAF- and ATF3-driven macrophages and CUX1- enriched fibroblast niches, that shape the epigenetic landscape of immunosuppressed tumors. These findings highlight the central role of innate immunity in shaping anti-tumor responses and offer potential therapeutic targets to enhance immunotherapy in this vulnerable patient population.

2026-08-07 | GSE316922 | GEO

Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer [scTCR-Seq]

Project description:The rising incidence of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), particularly among immunosuppressed individuals, underscores the need for a deeper understanding of the tumor microenvironment (TME) to develop effective and safe immunotherapies. This study employed single-cell multi-omic analyses to investigate the spatial distribution and transcriptional profiles of immune cells in NMSC from both immunocompetent (IC) and immunosuppressed (IS) patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. We found that IS tumors retain all requisite immune cell populations but display functional suppression and disrupted spatial organization. Our data revealed a limited number of distinct programs, particularly in macrophages and their spatially organized niches, that are linked to restricted T-cell repertoire diversity and impaired clonal expansion, providing a mechanistic bridge between innate dysfunction and adaptive immune failure. These perturbations were further confirmed by a novel spatial epigenomic atlas of the NMSC TME that revealed immune status–specific regulatory programs, including MAF- and ATF3-driven macrophages and CUX1- enriched fibroblast niches, that shape the epigenetic landscape of immunosuppressed tumors. These findings highlight the central role of innate immunity in shaping anti-tumor responses and offer potential therapeutic targets to enhance immunotherapy in this vulnerable patient population.

2026-08-07 | GSE318638 | GEO

Deciphering dermatological distinctions: Cornulin as a discriminant biomarker between Basal Cell Carcinoma and Squamous Cell Carcinoma detected through E-biopsy and Machine Learning

Project description:Background: Clinical misdiagnosis between cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) poses treatment challenges and carries risks of recurrence, metastases, and increased morbidity and mortality. Objective: We aimed to identify discriminant proteins markers for cSCC and BCC using a minimally invasive proteome sampling method called e-biopsy, employing electroporation for non-thermal cell permeabilization and machine learning. Methods: E-biopsy facilitated ex vivo proteome extraction from 21 cSCC and 21 BCC pathologically validated human cancers. LC/MS/MS profiling of 126 proteomes was followed by Machine Learning analysis to identify proteins distinguishing cSCC from BCC. For identified panel validation, we used proteomes sampled by e-biopsy from unrelated 20 cSCC and 46 BCC human cancers, and differential expression analysis of published transcriptomics. The most commonly chosen discriminant biomarker by machine learning models, cornulin, was also validated using fluorescent immunohistochemistry. Results: 192 proteomes sampled from 108 patients were analyzed. Machine Learning-based approaches resulted in a set of 11 potential biomarker proteins that can be used to construct a model with 95.2% average cross-validation accuracy, BCC precision of 93.6±14.5%, cSCC precision of 98.4±7.2%, specificity of 97.7±11.8%, and per-patient sensitivity 92.7±15.3%. Protein-protein interaction analysis revealed a novel interaction network connecting 10 of the 11 resulted proteins. Histological and transcriptomic validation confirmed cornulin as a discriminant marker significantly lower in cSCC than in BCC. Conclusions: E-biopsy combined with machine learning provides a novel approach to molecular biomarkers sampling from skin for biomarker detection and differential expression analysis between cSCC and BCC

2024-08-22 | PXD050713 | Pride

Differential expression analysis of cutaneous squamous cell carcinoma and basal cell carcinoma proteomic profiles sampled with e-biopsy

Project description:Clinical misdiagnosis between cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) affects treatment plans and carries risks of potential for recurrence, metastases, morbidity and mortality. We report the development of a novel tissue sampling approach with molecular biopsy using electroporation. This method, coined e-biopsy, enables non-destructive non-thermal permeabilization of cells in the skin for efficient vacuum-assisted extraction of informative biomolecules for rapid diagnosis. We used e-biopsy for ex vivo proteome extraction from 3 locations per patient in 21 cSCC and 20 BCC pathologically validated human tissue samples. The total 123 extracted proteomes were profiled using LC/MS/MS. The obtained mass spectra presented significantly different proteome profiles for cSCC and BCC with several hundreds of proteins significantly differentially expressed in each tumor in comparison to the other. Notably, our study showed that proteomes sampled with e-biopsy from cSCC and BCC lesions are different, and that 7 proteins were significantly overexpressed in BCC in comparison to cSCC even after the Bonferroni correction (FDR=7.1e-03). Our results provide evidence that the e-biopsy approach could potentially be used as a tool to support cutaneous tumors classification with rapid molecular profiling.

2024-08-22 | PXD046711 | Pride

Molecular classification of non-melanoma skin cancer by gene expression profiling

Project description:Non-melanoma skin cancers (NMSC) including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are more common kinds of skin cancer. Although these tumors share common pathological and clinical features, their similarity and heterogeneity at molecular levels are not fully elaborated yet. Here, by performing comparative analysis of gene expression profiling of BCC, SCC, and normal skin tissues, we could classify the BCC into three subtypes of classical, SCC-like, and normal-like BCCs. Functional enrichment and pathway analyses revealed the molecular characteristics of each subtype. The analysis of gene expression profiling among non-melanoma skin cancer types

2014-12-13 | E-GEOD-53462 | biostudies-arrayexpress

Molecular classification of non-melanoma skin cancer by gene expression profiling

2014-12-13 | GSE53462 | GEO

Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling

Project description:Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to investigate the transcriptomes of cSCC and actinic keratoses (AK), to elucidate key differences between precursor AK lesions and invasive carcinoma. This study identified 196 genes that are differentially expressed between AK and cSCC, with enrichment for processes including epidermal differentiation, cell migration, cell cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the MAPK pathway in the transition from AK to cSCC. Furthermore, the differentiation status of the tumor influenced the gene expression profile, which may have implications for drug sensitivity and response in clinical trials. These data indicate that progression to cSCC is associated with a complex pattern of molecular changes. We have identified relevant pathways involved in this process, in particular that the MAPK pathway may be pivotal to the transition from AK and may represent a potential therapeutic target. RNA was extracted by laser capture microdissection from 10 AK and 30 cSCC, for analysis using the Affymetrix HG U133 Plus 2.0 microarrays. The cSCC samples included a range of histological diagnoses (well differentiated through to poorly differentiatied) from both immunocompetent and immunosuppressed patients.

2014-01-21 | E-GEOD-45216 | biostudies-arrayexpress

Extracellular vesicles proteomic profile in anti-TNF immunosuppressed mice: insights into protein dysregulation during Leishmania infantum infection

Project description:Visceral leishmaniasis (VL) is most frequent in immunosuppressed patients, especially among those receiving immunosuppressive therapy for autoimmune diseases, being TNF antagonist (anti-TNF) one of the main immunosuppressants used. Under these conditions, VL is most severe, with lower response to traditional leishmanicidal treatments such as antimonials (Sb) and a higher risk of relapse. Extracellular vesicles (EVs) are a great source of biological molecules, including proteins, capable of modulating immune-mediated cells and virulence factors. To identify proteins involved in the clinic of VL under anti-TNF immunosuppression, the proteomic profile of EVs from the serum of BALB/c mice was analysed using a label-free quantification (LFQ) proteomics approach. In infected mice with Leishmania infantum a comparison was made between immunosuppression with anti-TNF at clinical doses and non-immunosuppressed conditions, before and after treatment with Sb. Proteomics analysis revealed 271 dysregulated proteins in the pre-treatment groups, the majority of which were downregulated in the anti-TNF samples. On the other hand, 216 proteins were identified in the treated groups, being most of them enriched in the anti-TNF treated (anti-TNF+Sb) samples. The gene ontology (GO) analysis of these proteins revealed altered pathways related to the immune system, liver regeneration, or ion transport. Our results show dysregulated proteins associated with anti-TNF immunosuppression, which could have an impact on the greatest severity of the VL infection experienced in this situation. This study is an important step in the understanding of the clinical management of these VL pharmacologically immunosuppressed cases.

2025-07-22 | PXD060935 | Pride

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