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Original Investigation
September 5, 2019

Prognostic Value of Tumor-Infiltrating Lymphocytes in Head and Neck Squamous Cell Carcinoma

Author Affiliations
  • 1Department of Otolaryngology, University of Michigan Medical School, Ann Arbor
  • 2Center for Cancer Biostatistics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor
  • 3Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor
  • 4Department of Pathology, University of Michigan Medical School, Ann Arbor
JAMA Otolaryngol Head Neck Surg. Published online September 5, 2019. doi:10.1001/jamaoto.2019.2427
Key Points

Question  What is the prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma?

Findings  In this cohort study that included 464 patients, higher levels of TILs were associated with improved survival in multivariable models.

Meaning  Scoring of TILs could be included into clinicopathologic prognostic models for patients with head and neck squamous carcinoma.


Importance  Biomarkers that reflect prognosis and cellular immunity in patients with head and neck squamous cell carcinoma (HNSCC) are a prerequisite for improving individualized treatment that limits the intensity and morbidity of conventional treatment and may be useful in the introduction of new immunotherapy regimens.

Objective  To determine if specific classes of tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens have prognostic value for outcomes in a large training and validation cohort of patients with HNSCC.

Design, Setting, and Participants  In this prospective, epidemiologic study with a median follow-up of 47.5 months, in 464 previously untreated patients with available tissue for construction of tissue microarray, HNSCC disease sites included oral cavity (228), oropharynx (147), larynx (74), and hypopharynx (15). The training cohort consisted of 241 patients and the validation cohort consisted of 223 patients. Overall tumor stage was I (55), II (69), III (71), or IV (269). Patients were enrolled between November 2008 to October 2014. Data were analyzed between October 2018 and April 2019.

Main Outcomes and Measures  Semiquantitative levels of CD4, CD8, and FoxP3 lymphocytes were assessed by immunohistologic analysis and correlations with clinical prognostic factors, initial treatment modality, and overall survival (OS) and disease-specific (DSS) survival were determined. A principal component analysis was performed to generate a combined TIL-weighted sum score (TILws).

Results  Of the 464 participants, 135 (29%) were women; mean (SD) age, 61.1 (11.8) years. Higher CD8 counts were associated with improved OS in both training and validation sets (HR, 0.94; 95% CI, 0.90-0.98 and HR, 0.97; 95% CI 0.95-0.99, respectively). Higher TILws were associated with improved OS and DSS in both the training set (HR, 0.91; 95% CI, 0.86-0.96; and HR, 0.93; 95% CI, 0.87-0.99, respectively) and validation set (HR, 0.96; 95% CI, 0.93-0.99; and HR, 0.94; 95% CI, 0.89-0.99, respectively). A multivariable Cox model controlling for batch, age, clinical stage, disease site, comorbidities, HPV status, and smoking, showed that higher TILws levels were associated with improved OS and DSS (HR, 0.94; 95% CI, 0.92-0.97; and HR, 0.94; 95% CI, 0.90-0.98, respectively). When grouped by treatment (surgery vs chemoradiation) and tested for interaction, treatment was found to be an effect modifier for CD4 levels and OS. Low CD4 levels were showed greater association with decreased survival in the chemoradiation cohort than the surgery cohort.

Conclusions and Relevance  The findings from this large cohort study suggest that levels of TILs are an independent prognostic factor in patients with HNSCC. Subsets of TILs and combined TIL scores may be clinically useful predictive and prognostic factors.

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