Tertiary Lymphoid Structure Raises Survival and Immunotherapy in HPV^- HNSCC

Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 has been used for the treatment of head and neck squamous cell carcinoma (HNSCC). However, the overall response rate to ICB therapy for HNSCC remains less than 20%. It has recently been reported that the appearance of tertiary lymphoid structures (TLSs) in tumor tissue is correlated with better prognosis and response to ICB treatment. Here, we demonstrated an immune classification for the tumor microenvironment (TME) of HNSCC by analyzing The Cancer Genome Atlas (TCGA)-HNSCC data set and found that immunotype D with TLS enrichment had a better prognosis and response to ICB treatment. Furthermore, we observed that TLSs were present in a part of tumor samples of human papillomavirus (HPV) infection negative HNSCC (HPV^- HNSCC) and were associated with the densities of dendritic cell (DC)-LAMP⁺ DCs, CD4⁺ T cells, CD8⁺ T cells, and progenitor T cells in TME. We established an HPV^- HNSCC mouse model with TLS-enriched TME by overexpressing LIGHT in a mouse HNSCC cell line. We found that the induction of TLS formation enhanced the response to PD-1 blockade treatment in the HPV^- HNSCC mouse model, accompanied by increases in DCs and progenitor exhausted CD8⁺ T cells in the TME. Elimination of CD20⁺ B cells attenuated the therapeutic effect of PD-1 pathway blockade in TLS⁺ HPV^- HNSCC mouse models. These results indicate that TLSs contribute to the favorable prognosis and antitumor immunity of HPV^- HNSCC. Inducing TLS formation in HPV^- HNSCC tumors is a potential therapeutic method for improving the ICB response rate in patients with HPV^- HNSCC.