Abstract 4923: The impact of HPV on oropharyngeal cancer tumor microenvironment and survival

Esther Lam; Jia Y. Wan; Rachel Bolanos; Brenda Y. Hernandez; Charles F. Lynch; Robert A. Edwards; Anil K. Chaturvedi; Adrian J. Correa; Arjan Diepstra; Wendy Cozen

doi:10.1158/1538-7445.AM2025-4923

The increased incidence of oropharyngeal squamous cell carcinoma (OPSCC) is attributed to increased human papillomavirus (HPV) infections. HPV-positive (HPV+) OPSCC has a better prognosis than HPV-negative (HPV-) OPSCC, highlighting the need to understand the determinants of this difference. The tumor microenvironment (TME) is associated with OPSCC prognosis, but differences due to HPV infection in OPSCC and the impact on survival are not well understood. To address this, de-identified formalin-fixed paraffin-embedded (FFPE) tumor blocks from 191 multiethnic OPSCC patients diagnosed from 1984-2004 were collected from three population-based cancer registries in the Surveillance, Epidemiology, and End Results Residual Tissue Repositories (Los Angeles, Hawai’i, and Iowa). HPV16 status was extracted from an earlier study (Chaturvedi et al, 2011) using in-situ hybridization (ISH) and line probe assays (LiPA), and HPV- tumors were further confirmed using p16 INK4a immunohistochemistry (IHC). Specimens that were ISH/LiPA negative and p16 positive were excluded (n=24). Sections were stained for CD3, CD8, CD163, B2M (HLA-I), and HLA-DP/DQ (HLA-II), using IHC. Counts of positive cells (CD3+, CD8+, and CD163+) were quantified using Visiopharm digital image analysis, while HLA stains were manually scored in tumor cells and used to identify dendritic cells (DC). Analysis of HPV16 tumor status and TME biomarker positive counts were compared using the nonparametric Mann-Whitney U test, and associations between the TME biomarkers and overall survival (OS) were analyzed using multivariable Cox regression to estimate the hazard ratio (HR) of TME biomarkers adjusted for age at diagnosis, sex, race/ethnicity, and SEER stage. There were 53 HPV+ and 114 HPV- patients included in the study after exclusions. Patients were primarily non-Hispanic white (56%) and male (80%); median age at diagnosis was 60. There were significantly higher levels of CD3+ (p<0.0001) and CD8+ (p<0.0001) T-cells in HPV+ compared to HPV- OPSCCs, and HPV+ tumors had reduced HLA-I expression (p<0.0001). High CD8+ T-cell levels were associated with better OS in HPV+ OPSCC (HR=0.21, p=0.036) but worse OS in HPV- OPSCC (HR=2.4, p=0.035). In HPV- tumors, HLA-II expression was associated with worse survival (HR=2.4, p=0.034), but HLA-II expression on DC in HPV+ tumors was strongly associated with improved survival (HR=0.07, P=0.025). In a subgroup (n=75; 36 HPV+, 39 HPV-), CD3+ and CD8+ T-cell infiltrations were higher in both tumoral (p<0.007; p<0.0001, respectively) and stromal areas (p=0.002; p<0.0001, respectively) of HPV+ compared to HPV- tumors. Higher stromal CD163+ macrophage infiltration was associated with worse OS in HPV+ tumors (HR= 4.3, p=0.030). These findings provide evidence that HPV+ OPSCC tumors have distinct TME profiles and associations with OS compared to HPV- OPSCC tumors and that the immune cell location within the TME is also important.

Abstract 4923: The impact of HPV on oropharyngeal cancer tumor microenvironment and survival

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