Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma
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.
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.
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.
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.
KeywordsCD103 Resident memory T-cell HNSCC Larynx
Adult Comorbidity Evaluation-27
American Joint Committee on Cancer
Head and neck squamous cell carcinoma
Laryngeal squamous cell carcinoma
Programmed cell death protein 1
JEM and JDS designed and performed experiments and wrote the manuscript. ACB and EB performed statistical analyses. PS, MM, SBC, AGS, KMM, KAC, SAM, JSM, GTW, CRB, MEP and TEC contributed to study design and sample procurement. JBM ensured quality of pathological specimens and tissue microarray. MES and JCB oversaw study design, execution, data analysis and manuscript drafts. All authors provided edits and approved of the final manuscript.
J. Chad Brenner received funding from NIH Grants U01-DE025184, P30-CA046592 and R01-CA194536. Thomas E. Carey received funding from NIH Grants U01-DE025184 and R01-CA194536. Jacqueline E. Mann was funded by NIH Grant F31-DE02760001. Joshua D. Smith received funding from NIH Grant T32-DC535615. J. Chad Brenner and Matthew E. Spector also received funding from the American Head and Neck Society.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no potential conflicts of interest relevant to this paper.
Ethical approval and ethical standards
This study was approved by the University of Michigan Hospital and Health Systems Institutional Review Board (HUM00081554).
The patients had provided informed consent to a prospectively maintained clinical epidemiology and tissue database.
- 20.Mandrekar JN, Mandrekar SJ, Cha SS (2003) Cutpoint determination methods in survival analysis using SAS. In: Proceedings of the 28th SAS users group international conference (SUGI) 261-28Google Scholar