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Objectives: The incidence of human papillomavirus positive oropharyngeal cancer (HPV+OPC) is increasing, and new biomarkers are required to better define prognostic groups and guide treatment. Infiltrating T cells have been well studied in head and neck cancer, however the presence and role of B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment has not, even though the interplay between T and B cells is increasingly being recognised., Materials and Methods: Using CD20 immunohistochemistry (IHC) to identify B cells and TLS in a cohort of 159 HPV + OPC patients, we semi-quantitatively scored abundance and location (intra-tumoral or stromal) and correlated findings with patient survival., Results: 32% (51/157) of patients had high intra-tumoral (IT) abundance of CD20 + B cells (≥5%) and this was prognostic for improved overall survival (OS) with an adjusted hazard ratio (HR) of 0.2 (95 % CI 0.0-0.7, p = 0.014). We validated our results in an independent cohort comprising 171 HPV + OPC where 14% (23/171) were IT CD20 + high, again showing improved survival with an adjusted HR for OS of 0.2 (95 % CI 0.0-1.4, p = 0.003). Neither stromal abundance nor the presence of TLS were prognostic in either cohort. B cells were subtyped by multispectral IHC, identifying CD20 + CD27 + cells, consistent with memory B cells, as the predominant subtype. Combined with validated biomarker CD103, a marker of tissue-resident memory T cells, IT CD20 + B cells abundance was able to prognostically stratify patients further., Conclusions: CD20 + B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We previously showed in human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV+OPSCC) that the presence of intratumoral (IT) PD-L1 + immune cells (ICs) or CD8 + infiltrating ICs are of prognostic value. Here we report the prognostic significance of these immune biomarkers in an independent validation cohort of 177 HPV+OPSCC patients. IT and stromal (S) localisation of PD-L1 + and CD8 + ICs were scored. High abundance (≥5%) of PD-L1 + IT ICs was found in 51/167 patients (30.5%) and was associated with improved overall survival (OS) (HR, 0.21; 95% CI, 0.05-0.91; P = 0. 012) validating our previous results. High abundance (≥30%) of CD8 + IT or S ICs, found in 77/167 patients (46.1%) provided a HR of 0.45 for OS however the confidence interval was wide (95% CI 0.16-1.25, p = 0.105). Multiplex immunohistochemistry revealed CD68 + macrophages and CD3 + CD8 + T cells to be the most common ICs expressing PD-L1. Gene expression analysis showed tumors with high abundance of PD-L1 + IT ICs exhibit gene signatures associated with responses to PD1 or PD-L1 inhibitors pembrolizumab and atezolizumab. These data support the role of immune biomarkers such as PD-L1 + ICs to identify subgroups of HPV+OPSCC patients with an excellent outcome that may be suitable for trials evaluating de-intensification of therapy., Competing Interests: Declaration of Competing Interest The authors make the following declaration of competing interests, all outside the submitted work: RY - institutional research funding, Roche; SP - advisory boards, MSD, Merck; honoraria, Celgene; DU - lecture fees, Bristol Myers Squibb (BMS); travel fees and lecture fees, Merck Sharp & Dohme (MSD); travel fees and lecture fees, Roche; CC - advisory boards, MSD (no honorarium); travel, accommodations and expenses, Pfizer, MSD; PN – honoraria, BMS; institutional research funding, BMS, Roche Genentech, Celgene-Juno, Advaxis, Compugen and Allergan; DR - institutional research funding, MSD, Merck, BMS, GSK, Roche, Regeneron, Amgen; Travel, MSD; advisory boards/trial steering committees (all uncompensated), MSD, Merck, BMS, GSK, Regeneron, Merck; BS – honoraria, BMS, AstraZeneca (Inst); consulting or advisory role, BMS, MSD, AstraZeneca, Pfizer, Genentech, Eisai; institutional research funding, Pfizer, Roche; royalties from Veristrat (Biodesix); UpToDate; travel, accommodation and expenses, AstraZeneca, Roche, Merck, BMS, Novartis. All remaining authors have declared no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)