Spatial and Single-Cell Transcriptomics Reveal a Cancer-Associated Fibroblast Subset in HNSCC That Restricts...

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Immunotherapy offers survival benefits for some head and neck squamous cell carcinoma (HNSCC) patients, but response rates are limited.
• Understanding mechanisms of CD8+ T-cell infiltration and dysfunction in the HNSCC tumor microenvironment is crucial for enhancing immunotherapy efficacy.

Purpose of the Study:

• To identify specific cancer-associated fibroblast (CAF) subsets that regulate CD8+ T-cell infiltration and function in HNSCC.
• To elucidate the role of these CAFs in immune evasion within the HNSCC tumor microenvironment.

Main Methods:

• Spatial transcriptomic analysis of HNSCC specimens with varying immune infiltration.
• Single-cell RNA sequencing of paired tumor and adjacent tissues.
• Analysis of CAF subsets expressing CXCLs, MHC-I, and galectin-9 (Gal9).

Main Results:

• Identified specific CAF subsets characterized by high expression of CXCLs, MHC-I, and Gal9.
• Found an inverse correlation between MHC-IhiGal9+ CAFs and a TCF1+GZMK+ CD8+ T-cell subset.
• Demonstrated that Gal9 on CAFs induces CD8+ T-cell dysfunction and reduces tumor-infiltrating T cells.

Conclusions:

• MHC-IhiGal9+ CAFs restrict CD8+ T-cell infiltration and function in HNSCC.
• These CAFs play a significant role in cancer immune evasion.
• Targeting these CAFs may improve immunotherapy outcomes for HNSCC.