Jacqueline E Mann1,2, Joshua D Smith1, Andrew C Birkeland1, Emily Bellile3, Paul Swiecicki4, Michelle Mierzwa5, Steven B Chinn1, Andrew G Shuman1, Kelly M Malloy1, Keith A Casper1, Scott A McLean1, Jeffery S Moyer1, Gregory T Wolf1,6, Carol R Bradford1,6, Mark E Prince1,6, Thomas E Carey1,6,7, Jonathan B McHugh2,6, Matthew E Spector8,9, J Chad Brenner10,11,12. 1. Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, 48109-0602, MI, USA. 2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA. 3. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. 4. Department of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. 6. Rogel Cancer Center, University of Michigan, 1500 E. Medical Center Dr., 1904 Taubman Center, 48109-5312, Ann Arbor, MI, USA. 7. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. 8. Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, 48109-0602, MI, USA. mspector@umich.edu. 9. Rogel Cancer Center, University of Michigan, 1500 E. Medical Center Dr., 1904 Taubman Center, 48109-5312, Ann Arbor, MI, USA. mspector@umich.edu. 10. Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, 48109-0602, MI, USA. chadbren@umich.edu. 11. Rogel Cancer Center, University of Michigan, 1500 E. Medical Center Dr., 1904 Taubman Center, 48109-5312, Ann Arbor, MI, USA. chadbren@umich.edu. 12. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. chadbren@umich.edu.
Abstract
BACKGROUND: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC. METHODS: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC. RESULTS: High tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC. CONCLUSIONS: An immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.
BACKGROUND: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC. METHODS: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC. RESULTS:High tumorCD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC. CONCLUSIONS: An immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.
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