Spatial and Single-Cell Transcriptomics Reveal a Cancer-Associated Fibroblast Subset in HNSCC That Restricts Infiltration and Antitumor Activity of CD8+ T Cells.
Spatial and Single-Cell Transcriptomics Reveal a Cancer-Associated Fibroblast Subset in HNSCC That Restricts Infiltration and Antitumor Activity of CD8+ T Cells.
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DOI：
10.1158/0008-5472.can-23-1448
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发表时间：
2024-01-16
期刊：
影响因子：
11.2
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中科院分区：
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空间分析确定了干扰素诱导的MHC-IhiGal9+CAF形成了CD8+T细胞的陷阱，为调节T细胞渗透和功能的肿瘤微环境中的复杂网络提供了洞察力。虽然免疫治疗可以延长一些头颈部鳞状细胞癌(HNSCC)患者的生存时间，但应答率仍然很低。阐明调控CD8+T细胞在肿瘤微环境中的渗透和功能障碍的关键机制有助于最大限度地发挥免疫疗法治疗HNSCC的益处。在这里，我们对不同免疫浸润的HNSCC标本进行了空间转录分析，并对五对肿瘤和邻近组织进行了单细胞RNA测序，揭示了与CD8+T细胞浸润限制和功能障碍相关的特定癌症相关成纤维细胞(CAF)亚群。这些CAF高表达CXCL(CXCL9、CXCL10和CXCL12)和MHC-I，并富含Galectin-9(Gal9)。MHC-IhiGal9+CAF的比例与TCF1+GZMK+CD8+T细胞亚群的丰度呈负相关。CAF上的Gal9诱导CD8+T细胞功能障碍，降低肿瘤浸润性TCF1+CD8+T细胞比例。总之，MHC-IhiGal9+CAF的鉴定促进了对CAF在癌症免疫逃避中的确切作用的理解，并为更有效的HNSCC免疫治疗铺平了道路。空间分析确定了干扰素诱导的MHC-IhiGal9+CAF形成了CD8+T细胞的陷阱，为调节T细胞渗透和功能的肿瘤微环境中的复杂网络提供了洞察力。
Spatial analysis identifies IFN-induced MHC-IhiGal9+ CAFs that form a trap for CD8+ T cells, providing insights into the complex networks in the tumor microenvironment that regulate T-cell infiltration and function. Although immunotherapy can prolong survival in some patients with head and neck squamous cell carcinoma (HNSCC), the response rate remains low. Clarification of the critical mechanisms regulating CD8+ T-cell infiltration and dysfunction in the tumor microenvironment could help maximize the benefit of immunotherapy for treating HNSCC. Here, we performed spatial transcriptomic analysis of HNSCC specimens with differing immune infiltration and single-cell RNA sequencing of five pairs of tumor and adjacent tissues, revealing specific cancer-associated fibroblast (CAF) subsets related to CD8+ T-cell infiltration restriction and dysfunction. These CAFs exhibited high expression of CXCLs (CXCL9, CXCL10, and CXCL12) and MHC-I and enrichment of galectin-9 (Gal9). The proportion of MHC-IhiGal9+ CAFs was inversely correlated with abundance of a TCF1+GZMK+ subset of CD8+ T cells. Gal9 on CAFs induced CD8+ T-cell dysfunction and decreased the proportion of tumor-infiltrating TCF1+CD8+ T cells. Collectively, the identification of MHC-IhiGal9+ CAFs advances the understanding of the precise role of CAFs in cancer immune evasion and paves the way for more effective immunotherapy for HNSCC. Spatial analysis identifies IFN-induced MHC-IhiGal9+ CAFs that form a trap for CD8+ T cells, providing insights into the complex networks in the tumor microenvironment that regulate T-cell infiltration and function.