Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer

Purpose: Human papilloma virus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC and this is linked to dense tumor immune infiltration. Since the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in tumor microenvironment and clinical outcome. Experimental design: To this purpose an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 HPV16-positive and -negative OPSCC patients was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 HPV16-positive OPSCC patients present in the publicly available cancer genomic atlas database. Results: In 64% of the HPV16-positive tumors type 1 HPV16-specific T-cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size and less lymph node metastases but also to a type I oriented tumor microenvironment, including high numbers of activated CD161+ T-cells, CD103+ tissue-resident T-cells, dendritic cells (DC) and DC-like macrophages. Conclusions: The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process.