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The transcriptomic landscape of immuno-suppressed cutaneous squamous cell carcinoma patients
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O carcinoma de células escamosas cutâneo (cSCC) é o segundo cancro de pele mais comum. Embora geralmente tratável e associado a um baixo risco de metastização, a sua elevada incidência constitui um desafio clínico relevante, principalmente entre pacientes imunocomprometidos (IS), como os transplantados de órgãos (OTR) e os portadores de neoplasias hematológicas (HM). Em comparação com indivíduos imunocompetentes (IC), estes doentes desenvolvem cSCC com maior frequência e agressividade. No entanto, os mecanismos biológicos responsáveis por estas diferenças permanecem pouco compreendidos, uma vez que o cSCC tem sido há muito considerado um cancro de baixo risco, tendo limitado o seu estudo.
Neste trabalho, explorámos a maior coorte de doentes IS com cSCC analisada até à data, tendo alcançado três conclusões principais. Primeiro, os tumores de IS apresentaram uma atividade imunitária comprometida, incluindo perda de hallmarks imunitários, menor infiltração de células imunes, diferenciação defeituosa de linfócitos T e um desequilíbrio entre linfócitos T citotóxicos e fibroblastos associados ao cancro, com valor prognóstico para metastização. Em paralelo, exibiram uma agressividade intrínseca, traduzida pela sobre expressão de programas proliferativos e metabólicos, nomeadamente a transição epitelial-mesenquimal (EMT). Este padrão ajuda a explicar os piores desfechos associados ao cSCC em doentes IS. Segundo, identificámos um gradiente dentro do grupo IC, onde homens com tumores prévios exibiram perfis semelhantes aos dos pacientes IS. Este resultado evidenciou uma heterogeneidade desconhecida dentro do grupo, questionando o uso da atual dicotomia IC/IS na estratificação dos pacientes e sugerindo que alguns doentes IC podem estar mais próximos do estado imunocomprometido. Terceiro, embora as análises dos subgrupos de pacientes IS tenham sido condicionadas pelo poder estatístico, os resultados apontaram para trajetórias divergentes da doença: os doentes com HM apresentaram ativação da EMT e piores desfechos, enquanto que os OTR exibiram uma maior diferenciação epitelial e microambientes mais permissivos à resposta imunitária.
No geral, estes resultados fornecem novos contributos moleculares para compreender os mecanismos subjacentes à evolução mais agressiva do cSCC em doentes IS e evidenciam heterogeneidade entre pacientes IC. Sublinha-se também a necessidade de estratégias de estratificação mais robustas, capazes de identificar subgrupos biologicamente relevantes, com impacto direto no prognóstico e no delineamento de intervenções clínicas personalizadas.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although typically treatable and associated with a low risk of metastasis, its high incidence poses a significant clinical challenge, particularly among immunosuppressed (IS) individuals, such as organ transplant recipients (OTR) and patients with haematological malignancies (HM). Compared to immunocompetent (IC) patients, they develop cSCC more frequently and experience a more aggressive disease course. However, the biological mechanisms underlying these differences remain poorly understood, as cSCC has long been regarded as a low-risk malignancy and has therefore been understudied. Here, we leveraged the largest cohort of IS cSCC patients to date and reached three main findings. First, IS tumours showed impaired immune activity, including loss of immune-related hallmarks, reduced immune infiltration, defective T-cell differentiation, and an altered balance between cytotoxic T cells and cancer-associated fibroblasts (CAF), with prognostic value for metastasis. In parallel, they displayed intrinsic aggressiveness through enrichment of proliferative and metabolic programmes, notably the epithelial–mesenchymal transition (EMT). This dual pattern helps explain the worse outcomes associated with IS cSCC. Second, within the IC group, we identified a transcriptional gradient of immune competence, with males with prior cSCC tumours exhibiting IS-like profiles. This revealed hidden heterogeneity within the IC group and challenged the current IC/IS dichotomy used for patient stratification, as some IC patients may be closer to IS. Third, although subgroup analyses were limited by statistical power, they revealed distinct trajectories among IS patients: HM were characterised by EMT activation and worse outcomes, whereas OTR displayed epithelial differentiation and more immune-permissive micro-environments. Overall, these findings provide new molecular insights into the aggressive course of cSCC in IS patients, while also uncovering heterogeneity within the IC group. They highlight the need for stratification strategies that capture biologically meaningful subgroups, with direct implications for prognosis and personalised management.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although typically treatable and associated with a low risk of metastasis, its high incidence poses a significant clinical challenge, particularly among immunosuppressed (IS) individuals, such as organ transplant recipients (OTR) and patients with haematological malignancies (HM). Compared to immunocompetent (IC) patients, they develop cSCC more frequently and experience a more aggressive disease course. However, the biological mechanisms underlying these differences remain poorly understood, as cSCC has long been regarded as a low-risk malignancy and has therefore been understudied. Here, we leveraged the largest cohort of IS cSCC patients to date and reached three main findings. First, IS tumours showed impaired immune activity, including loss of immune-related hallmarks, reduced immune infiltration, defective T-cell differentiation, and an altered balance between cytotoxic T cells and cancer-associated fibroblasts (CAF), with prognostic value for metastasis. In parallel, they displayed intrinsic aggressiveness through enrichment of proliferative and metabolic programmes, notably the epithelial–mesenchymal transition (EMT). This dual pattern helps explain the worse outcomes associated with IS cSCC. Second, within the IC group, we identified a transcriptional gradient of immune competence, with males with prior cSCC tumours exhibiting IS-like profiles. This revealed hidden heterogeneity within the IC group and challenged the current IC/IS dichotomy used for patient stratification, as some IC patients may be closer to IS. Third, although subgroup analyses were limited by statistical power, they revealed distinct trajectories among IS patients: HM were characterised by EMT activation and worse outcomes, whereas OTR displayed epithelial differentiation and more immune-permissive micro-environments. Overall, these findings provide new molecular insights into the aggressive course of cSCC in IS patients, while also uncovering heterogeneity within the IC group. They highlight the need for stratification strategies that capture biologically meaningful subgroups, with direct implications for prognosis and personalised management.
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Cutaneous squamous cell carcinoma (cSCC) Immunosuppression (IS) Immunocompetence (IC) Organ transplant recipient (OTR) Haematological malignancy (HM) Metastasis