Single-cell profiling reveals the sustained immune infiltration, surveillance, and tumor heterogeneity of infiltrative BCC

Abstract Background Infiltrative basal cell carcinoma (iBCC) is a particularly aggressive subtype of BCC that tends to recur after surgery, and its progression and malignancy are closely related to its interaction with the local tumor microenvironment (TME). Methods Here, we performed single-cell RNA sequencing (scRNA-seq) from 5 patients to determine the dynamic changes of TME between iBCC and adjacent normal skin (ANS). Results We found active immune collaborations among CXCL13 + follicular helper-like T cells (Tfh-like cells), SPP1 + CXCL9/10 high Macro1, and plasma cells, which were enriched in iBCC. Specifically, SPP1 + CXCL9/10 high Macro1 could activate plasma cells by BAFF signaling, and Tfh-like cells potentially recruited B/Plasma cells through CXCL13. The proinflammatory SPP1 + CXCL9/10 high Macro1 and angiogenesis-related SPP1 + CCL2 high Macro1 were characterized, revealing their heterogeneous phenotype within the TME. We also discovered a novel iBCC-enriched ANGPT2 + lymphatic endothelial cell (LEC) subtype with strong abilities to promote leukocyte migration and activation. Interestingly, we found upregulation of MHC-I molecules in fibroblasts in iBCC compared to those in ANS. However, we found that MDK signals derived from malignant basal cells (MBCs) were markedly increased, and their expression was an independent factor in predicting the infiltration depth of iBCC, emphasizing its role in driving malignancy and remodeling the TME. Additionally, we identified differentiation-associated SOSTDC1 + IGFBP5 + CTSV + MB1 and epithelial mesenchyme transition (EMT)-associated TNC + SFRP1 + CHGA + MB2. The components of the two heterogeneous subpopulations in the TME might be effective predictors of the malignancy and prognosis of iBCC. Conclusions Altogether, our study is beneficial for understanding the cellular heterogeneity involved in the pathogenesis of iBCC and provides potential therapeutic targets for clinical research.