Abstract
BackgroundStandard 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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
In contrast to direct CD20+ B cell/CD8+ T cell interactions, no differences between human papillomavirus (HPV)-associated and HPV-negative samples were observed in the density of tertiary lymphoid structures (TLS) with germinal centers (Fig. 1e)
To evaluate the prognostic impact of tumor-infiltrating CD20+ B cells, CD8+ T cells, DC-LAMP+ DCs and B cell/ CD8+ T cell interactions in both intratumoral and stromal compartments of OPSCC samples, we investigated overall survival (OS) upon stratifying the patient cohort based on the median of positive cells per 1 mm2 of the tumor nest and the tumor stroma area
Summary
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. A better stratification of patients and the development of novel therapeutic protocols are crucially needed. The immune response has been suggested as a key factor in the better outcome of patients with HPV-associated tumors [7]. During the past two decades, extensive immuno-oncology research has been mainly focused on T cells and several studies have reported the association between a high density of tumor infiltrating T lymphocytes (TILs) and increased patient survival [8, 11,12,13]. Clinical trials with the above mentioned PD-1:PD-L1 targeting agents only reported modest response rates (13–23%) in HNSCC patients [14,15,16,17]. Novel immunotherapy targets and consequent effective therapeutic strategies are still needed for this type of carcinoma
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