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3117 Background: Low response rates in immune checkpoint blockade (ICB) treated head and neck squamous cell carcinoma (HNSCC)drive a critical need for robust clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in various types of cancer, including HNSCC; however, its predictive value for ICB response has not been investigated. Preclinical studies suggest K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors. Furthermore, knocking out K17 results in restored response to ICB in a HNSCC mouse model. Here, we evaluated if K17 protein expression predicts response to ICB in human HNSCC patients. Methods: We conducted a retrospective analysis of 26 HNSCC patients that received at least one cycle of pembrolizumab at the University of Wisconsin-Madison Carbone Cancer Center. Pretreatment, archival, formalin-fixed, paraffin-embeded samples were stained by immunohistochemistry using a K17 monoclonal antibody. Clinical outcomes were investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathology review, cases were categorized into K17 high vs K17 low based on a cut-off of > 5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component. Correlation between K17 expression and clinical outcomes was assesed using Fischer's exact test and log rank test. Results: The 26 patients included in this study were 85% male, median age 60.5 years, 74% ECOG performance status < 2, with 80% having received prior chemotherapy. Primary site included oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) showed high K17 expression, and 9 tumors (35%) showed low K17 expression. Eleven patients (42%) had programmed death ligand 1 (PD-L1)+ tumors as determined by combined positive score. Six patients (23%, all K17 low) achieved clinical benefit, while 20 patients (77%, 17 K17 high and 2 K17 low) had progressive disease. High K17 expression was associated with lack of clinical benefit (p < 0.001), shorter time to treatment failure (p < 0.001), progression-free (p = 0.004) and overall survival (p = 0.02). PD-L1 expression by immunohistochemistry (clone 22C3) did not correlate with K17 expression or clinical outcome. Conclusions: Our findings suggest that K17 expression may predict clinical benefit from ICB in HNSCC patients, thus supporting further validation studies. [Table: see text]