Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer

Hao Li, Meng-Jie Zhang, Boxin Zhang, Wen-Ping Lin, Shu-Jin Li, Dian Xiong, Qing Wang, Wen-Da Wang, Qi-Chao Yang, Cong-Fa Huang, Wei-Wei Deng () and Zhi-Jun Sun ()
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Hao Li: Wuhan University
Meng-Jie Zhang: Wuhan University
Boxin Zhang: Wuhan University
Wen-Ping Lin: Wuhan University
Shu-Jin Li: Wuhan University
Dian Xiong: Wuhan University
Qing Wang: Wuhan University
Wen-Da Wang: Wuhan University
Qi-Chao Yang: Wuhan University
Cong-Fa Huang: Wuhan University
Wei-Wei Deng: Wuhan University
Zhi-Jun Sun: Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Tumor tertiary lymphoid structures (TLS), especially mature TLS (mTLS), have been associated with better prognosis and improved responses to immune checkpoint blockade (ICB), but the underlying mechanisms remain incompletely understood. Here, by performing single-cell RNA, antigen receptor sequencing and spatial transcriptomics on tumor tissue from head and neck squamous cell carcinoma (HNSCC) patients with different statuses of TLS, we observe that mTLS are enriched with stem-like T cells, and B cells at various maturation stages. Notably, progenitor exhausted CD4+ T cells, with features resembling follicular helper T cells, support these responses, by activating B cells to produce plasma cells in the germinal center, and interacting with DC-LAMP+ dendritic cells to support CD8+ T cell activation. Conversely, non-mTLS tumors do not promote local anti-tumor immunity which is abundant of immunosuppressive cells or a lack of stem-like B and T cells. Furthermore, patients with mTLS manifest improved overall survival and response to ICB compared to those with non-mTLS. Overall, our study provides insights into mechanisms underlying mTLS-mediated intra-tumoral immunity events against cancer.

Date: 2025
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DOI: 10.1038/s41467-025-59341-w

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