Dissecting Tissue Compartment-Specific Protein Signatures in Primary and Metastatic Oropharyngeal Squamous Cell Carcinomas

Abstract

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in samples of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC.

Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy

“…However, we found higher levels of B7-H3 expression in both the tumor and stromal compartments of responders compared to non-responders. This finding is consistent with our previous published work on oropharyngeal squamous cell carcinoma (OPSCC), in which we demonstrated that B7-H3 expression in the stroma of nodal metastatic samples was associated with improved overall survival (OS) in patients ( 25 ). Here, we show that V-domain immunoglobulin suppressor of T cell activation (VISTA) was enriched in non-responders.…”

“…B7-H3 expression may be linked to immune suppression, which promotes tumor cell growth. Recent studies have found that in a number of solid tumors, including breast, ovarian, brain, and gastric cancer, as well as Merkel cell carcinoma, showed that high expression of B7-H3 increased tumor size, invasion, and proliferation, which were linked to worse prognosis and overall survival (24). However, we found higher levels of B7-H3 expression in both the tumor and stromal compartments of responders compared to non-responders.…”