Correlation of cellular immunity with human papillomavirus 16 status and outcome in patients with advanced oropharyngeal cancer

Abstract

Objective: to determine whether the favorable outcome associated with human papillomavirus (HPV) 16-positive oropharyngeal cancer is related to a patient's adaptive immunity.

Setting: academic medical center.

Patients: forty-seven of 66 previously untreated patients (6 of 20 patients with stage III and 41 of 46 with stage IV cancer) in a prospective clinical trial of chemoradiotherapy.

Intervention: all patients were treated with a single course of neoadjuvant chemotherapy followed by either surgery (for nonresponders) or chemoradiotherapy.

Main outcome measures: pretreatment levels (percentages and absolute counts) of CD3, CD4, CD8, natural killer, and B cells and overall white blood cell counts were measured by flow cytometry. Correlations of subsets with HPV-16 status, tumor subsite, cancer stage, T class, N class, smoking status, performance status, sex, response to chemoradiotherapy, p53 mutation type, epidermal growth factor receptor expression, and disease-specific and overall survival were determined.

Results: after a median follow-up of 6.6 years, improved survival was associated with an elevated percentage of CD8 cells (P = .04), a low CD4:CD8 ratio (P = .01), low epidermal growth factor receptor expression (P = .002), and HPV status (P = .02). The percentage of CD8 cells was significantly higher (P = .04) and the CD4:CD8 ratio was significantly lower (P = .02) in HPV-16-positive patients. A higher percentage of CD8 cells was associated with response to induction chemotherapy (P = .02) and complete tumor response after chemoradiotherapy (P = .045).

Conclusion: these findings confirm previous correlations of outcome with circulating CD8 cell levels and support the conjecture that improved adaptive immunity may play a role in the favorable prognosis of patients with HPV-16-positive cancers.

Figure 1

Levels of T lymphocytes (A) and CD4:CD8 ratios (B) according to human papillomavirus (HPV) status. The mean (SEM) percentage of CD8 cells was significantly elevated (P=.04), and the CD4:CD8 ratio was significantly lower (P=.02) in HPV-16-positive patients compared with HPV-16-negative patients. Significance was determined by the Wilcoxon rank sum test.

Figure 2

Levels of T Lymphocyte levels by human papillomavirus (HPV) 16 and smoking status. The mean (SEM) percentage of CD8 cells was significantly elevated in HPV-16-positive smokers and nonsmokers compared with HPV-16-negative smokers (P=.04, Spearman rank correlation)

Figure 3

Peripheral blood levels of T lymphocytes (A) and CD4:CD8 ratios (B) according to tumor response to induction chemotherapy. The mean (SEM) percentage of CD8 cells was significantly higher (P=.02) and the CD4:CD8 ratio was significantly lower (P=.02) in responders to induction chemotherapy. Significance was determined by the Wilcoxon rank sum test.

Figure 4

Overall survival of patients positive for human papillomavirus (HPV) 16 is improved compared to patients with HPV-16-negative cancers (P=.005).

Figure 5

Overall survival of patients using previously established cut points for the percentage of CD8 cells (A) and for CD4:CD8 ratios (B). Improved overall survival in patients tended to be associated with high perectange of CD8 cells and a low CD4:CD8 ratio (P=.14 and P=.11, respectively)