CXCL16 Producing Tumor Clones Are Shaping Immunosuppressive Microenvironment in Squamous Cell Carcinoma via CXCR6 Regulatory T Cell

CXCL16 Producing Tumor Clones Are Shaping Immunosuppressive Microenvironment in Squamous Cell Carcinoma via CXCR6 Regulatory T Cell

ABSTRACT Background Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are the most prevalent types of nonmelanoma skin cancer (NMSC) and exhibit significant inter‐ and intra‐tumor heterogeneity. cSCC has a higher metastatic potential than BCC, accompanied by a considerable mort...

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Main Authors: Hyun Seung Choi, Sunyoung Jung, Ki‐Myo Kim, Mihyun Lee, Jun Ho Park, Sanha Hwang, Seung Min Cha, Jade N. Young, Dina Poplausky, Hyunsung Nam, Nicholas Gulati, Chung‐Gyu Park, Hyun Je Kim, Ji‐Ung Park
Format: Article
Language:English
Published: Wiley 2025-08-01
Series:Cancer Medicine
Subjects:
basal cell carcinoma
cutaneous squamous cell carcinoma
scRNA and TCR seq
spatial transcriptomic
Online Access:https://doi.org/10.1002/cam4.71060
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Summary:ABSTRACT Background Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are the most prevalent types of nonmelanoma skin cancer (NMSC) and exhibit significant inter‐ and intra‐tumor heterogeneity. cSCC has a higher metastatic potential than BCC, accompanied by a considerable mortality rate. However, the detailed mechanisms of tumor evolution in cSCC have not yet been described. Methods We performed single‐cell RNA sequencing (scRNA‐seq) and T cell receptor (TCR) clonal analysis of skin biopsies from five BCCs, three squamous cell carcinomas in situ (SCCIS), and two invasive squamous cell carcinomas (SCC). Independent SCC specimens were used for spatial transcriptomic (ST) analysis using GeoMx Digital Spatial Profiler (DSP). Result Using scRNA‐seq, we analyzed a total of 117,663 cells. We distinguished cancer cells using copy number variation and identified SCC‐specific genes that potentially contribute to tumor progression. Analysis of tumor clones revealed SCC‐specific COL6A1+/ITGA5+ carcinoma cells which produce CXCL16. We also annotated CXCR6+ regulatory T cells (Tregs) which potentially move toward the tumor site by CXCL16, shaping the immunosuppressive TME. ST analysis supported these clones were located at the invasion site of SCC. Conclusion We suggest COL6A1 and ITGA5 promote the invasive and metastatic property of SCC. We also uncovered how SCC recruits Tregs via the CXCL16/CXCR6 axis to create a TME favorable for its survival. These molecules can be used as potential therapeutic targets for treatment of SCC.
ISSN:2045-7634

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