Deciphering the interplay of HPV infection, MHC-II expression, and CXCL13 CD4 T cell activation in oropharyngeal cancer: implications for immunotherapy.

BACKGROUND

Human papillomavirus (HPV) infection has become an important etiological driver of oropharyngeal squamous cell carcinoma (OPSCC), leading to unique tumor characteristics. However, the interplay between HPV-associated tumor cells and tumor microenvironment (TME) remains an enigma.

METHODS

We performed a single-cell RNA-sequencing (scRNA-seq) on HPV-positive (HPV) and HPV-negative (HPV) OPSCC tumors, each for three samples, and one normal tonsil tissue. Ex vivo validation assays including immunofluorescence staining, cell line co-culture, and flow cytometry analysis were used to test specific subtypes of HPV tumor cells and their communications with T cells.

RESULTS

Through a comprehensive single-cell transcriptome analysis, we uncover the distinct transcriptional signatures between HPV and HPV OPSCC. Specifically, HPV OPSCC tumor cells manifest an enhanced interferon response and elevated expression of the major histocompatibility complex II (MHC-II), potentially bolstering tumor recognition and immune response. Furthermore, we identify a CXCL13CD4 T cell subset that exhibits dual features of both follicular and pro-inflammatory helper T cells. Noteworthily, HPV OPSCC tumor cells embrace extensive intercellular communications with CXCL13CD4 T cells. Interaction with HPV OPSCC tumor cells amplifies CXCL13 and IFNγ release in CD4T cells, fostering a pro-inflammatory TME. Additionally, HPV tumor cells expressing high MHC-II and CXCL13CD4 T cell prevalence are indicative of favorable overall survival rates in OPSCC patients.

CONCLUSIONS

Together, our study underscores a synergistic inflammatory immune response orchestrated by highly immunogenic tumor cells and CXCL13CD4 T cells in HPV OPSCC, offering useful insights into strategy development for patient stratification and effective immunotherapy in OPSCC.