BACKGROUND: Standard treatment of oropharyngeal squamous cell carcinoma (OPSCC) is associated with high morbidity, whereas immunotherapeutic approaches using PD-1:PD-L1 checkpoint blockade only show moderate response rates in OPSCC patients. Therefore, a better stratification of patients and the development of novel therapeutic protocols are crucially needed. The importance of tumor-infiltrating B cells (TIL-Bs) in shaping antitumor immunity remains unclear; therefore, we analyzed frequency, phenotype, prognostic value and possible roles of TIL-Bs in OPSCC. METHODS: We utilized transcriptomic analysis of immune response-related genes in 18 OPSCC samples with respect to human papillomavirus (HPV) status. The density and localization of CD20+, CD8+ and DC-LAMP+ cells were subsequently analyzed in 72 tissue sections of primary OPSCC samples in relation to patients' prognosis. The immunohistochemical approach was supplemented by flow cytometry-based analysis of phenotype and functionality of TIL-Bs in freshly resected primary OPSCC tissues. RESULTS: We observed significantly higher expression of B cell-related genes and higher densities of CD20+ B cells in HPV-associated OPSCC samples. Interestingly, CD20+ TIL-Bs and CD8+ T cells formed non-organized aggregates with interacting cells within the tumor tissue. The densities of both intraepithelial CD20+ B cells and B cell/CD8+ T cell interactions showed prognostic significance, which surpassed HPV positivity and CD8+ TIL density in stratification of OPSCC patients. High density of TIL-Bs was associated with an activated B cell phenotype, high CXCL9 production and high levels of tumor-infiltrating CD8+ T cells. Importantly, the abundance of direct B cell/CD8+ T cell interactions positively correlated with the frequency of HPV16-specific CD8+ T cells, whereas the absence of B cells in tumor-derived cell cultures markedly reduced CD8+ T cell survival. CONCLUSIONS: Our results indicate that high abundance of TIL-Bs and high density of direct B cell/CD8+ T cell interactions can predict patients with excellent prognosis, who would benefit from less invasive treatment. We propose that in extensively infiltrated tumors, TIL-Bs might recruit CD8+ T cells via CXCL9 and due to a highly activated phenotype contribute by secondary costimulation to the maintenance of CD8+ T cells in the tumor microenvironment.

Department of Oncology and Radiotherapy Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Otorhinolaryngology and Head and Neck Surgery Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

SOTIO a s Jankovcova 1518 2 CZ 17000 Prague 7 Prague Czech Republic

SOTIO a s Jankovcova 1518 2 CZ 17000 Prague 7 Prague Czech Republic Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

SOTIO a s Jankovcova 1518 2 CZ 17000 Prague 7 Prague Czech Republic Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Hradec Králové Czech Republic

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