Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8(+) T cells
Abstrakt
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.