Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer
Tertiary lymphoid structures (TLS) especially mature TLS (mTLS), present within the tumor, have been associated with improved outcomes and responses to immune checkpoint blockade (ICB), but the underlying mechanisms remain incompletely understood. Here, we performed single-cell RNA and antigen receptor sequencing and spatial transcriptomics on patients with head and neck squamous cell carcinoma (HNSCC) with different statuses of TLS. We observe that mTLS are enriched with stem-like T cells, as well as B cells at various maturation stages, supporting the generation of T and B cell responses in the tumor microenvironment (TME). Notably, CD4+ progenitor exhausted T cells, with features resembling follicular helper T cells, play a crucial role in these responses within mTLS, which can both activate B cells to produce plasma cells in the germinal center, and work with DC-LAMP+ dendritic cells to support the activation of CD8+ T cells. Conversely, non-mTLS tumors do not promote local anti-tumor immunity due to an abundance of immunosuppressive cells or a lack of stem-like B and T cells. Furthermore, patients with mTLS have shown significantly improved overall survival and response to ICB treatment for HNSCC. Overall, our study provides insights into mechanisms underlying mTLS-mediated intra-tumoral immunity cycle against cancer.