Abstract Introduction and aims Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with complex immune interactions within the tumour microenvironment (TME). Understanding the TME in cSCC can reveal cellular and molecular signatures that influence disease progression and treatment response, including immunotherapy. Methods Using single-cell RNA sequencing (scRNAseq) of 88 000 cells from 10 cSCC and 5 perilesional normal skin samples, we identified 41 immune cell subtypes. Results Among CD8+ T cells, four cytotoxic subpopulations were found. Notably, a Granzyme K (GZMK)-expressing subpopulation emerged as a key player, particularly in the context of immune checkpoint blockade therapy. This GZMK CD8+ T-cell subpopulation was expanded in cSCC compared with perilesional skin. Moreover, the GZMK signature was significantly upregulated in high-risk cSCC with greater metastatic potential, and a high T effector GZMK signature score was associated with poorer metastasis-free survival (multivariate analysis adjusting for age, sex and clinical stage hazard ratio = 1.60, P = 0.05). Consistent with previous findings, we also observed a higher abundance of exhausted CD8+ T cells in cSCC relative to perilesional skin, with exhaustion signatures correlating with disease progression. To explore potential repressors of GZMK CD8+ T-cell cytotoxicity, we performed cell–cell communication analysis, identifying subsets of conventional dendritic cells (cDCs) and activated regulatory T cells (Tregs) as likely suppressors within the TME. Spatial transcriptomics using 10X Visium revealed increased infiltration and colocalization of GZMK cells and cDCs into malignant regions of high-risk tumours compared with low-risk ones. Conclusions These findings deepen our understanding of the immunosuppressive landscape in cSCC and highlight potential therapeutic targets to enhance immunotherapy efficacy by overcoming inhibitory signals.
Patel et al. (Tue,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: