Infiltrating lymphocytes and human papillomavirus-16--associated oropharyngeal cancer

Abstract

Objectives/hypothesis: Human papillomavirus-16 (HPV-16)-associated carcinoma of the oropharynx has a favorable prognosis. Such patients have elevated CD8+ T-lymphocyte levels that correlate with response to chemotherapy and survival. Tumor-infiltrating lymphocyte (TIL) subpopulations were assessed in pretreatment biopsies from a prospective patient cohort to determine if TIL subsets differed by HPV status, clinical factors, or patient outcome or correlated with peripheral blood T-cell levels.

Study design: Retrospective immunological correlative study of patients entered in a prospective Phase 2 clinical trial.

Methods: Measured were CD8, CD4, CD68, and Treg (FoxP3) lymphocytes by immunohistochemistry in a tissue microarray created from patients (n=46) with advanced oropharyngeal cancer. Correlations with peripheral blood levels, HPV status, expression of epidermal growth factor receptor (EGFR), clinical tumor, and patient characteristics and outcome were determined. Median follow-up was 6.6 years.

Results: HPV-16-positive patients had improved survival (P=.016). Degree of T-cell infiltration did not differ by HPV status but was significantly related to disease-specific survival (DSS) and overall survival (OS). Even after adjusting for HPV status, we found that CD8, FoxP3, and total T cells were significantly associated with DSS (P=.0236, P=.0040, and P=.0197, respectively) and OS (P=.0137, P=.0158, and P=.0115, respectively). Less T-cell infiltration (P=.0130) and CD4 cells in particular (P=.0792) were associated with higher EGFR expression.

Conclusions: Improved outcomes are associated with increased TILs independent of HPV status and suggest the local immune response may be more related to factors such as tumor size, EGFR expression, or performance status than HPV status. Further study of larger numbers of patients and infiltrates combined with functional analysis of individual subsets may be necessary to detect significant differences in local immunity in HPV-16-related cancers.