Background: There is an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) due to human papillomavirus (HPV). Patients with HPV + OPSCC tend to have an excellent prognosis, however, a subset of patients develops unresectable recurrent or distant metastatic (R/M) disease. CD8+ cytotoxic T lymphocytes are potent effectors in the tissue microenvironment and are essential for anti-tumor immunity. HPV related tumors exhibit high degrees of immune infiltration, which is associated with improved survival and response to immune checkpoint inhibitors (ICIs). The prognostic significance of CD8+ tumor infiltrating lymphocytes (TILs) on survival and response to ICIs in patients with R/M HNSCC has not been well studied.
Methods: A retrospective case series was performed of patients diagnosed with R/M HNSCC who had biopsies performed of any metastatic deposit at the time of R/M diagnosis. Levels of CD8+ TILs were quantified on a tissue microarray. Patients were dichotomized into low versus high CD8+ TIL counts based on the median. Differences in TIL counts based on HPV status and primary tumor site were assessed using T tests and one way ANOVA. Kaplan- Meier and log rank tests were performed to determine survival estimates. Cox regression analysis was performed to determine if CD8+ TILs were predictive of survival outcomes after controlling for HPV status. Treatment duration on ICIs was compared between patients with high and low CD8+ TILs using T test.
Results: Biopsies of metastatic deposits from 79 patients were evaluated on the tissue microarray. Patients with HPV + disease (n=17) had higher TIL counts compared to HPV – patients (HPV+ mean TIL count = 108 (SD 163) vs 38 (SD 45), p<0.01). Mean TIL counts were higher for patients with primary tumors in the oropharynx (n=33) compared to the oral cavity (N=26), larynx (n=13), and cutaneous sites (n=4), however this was not statistically significant (oropharynx mean TIL count = 92 (SD 126), oral cavity = 52 (SD 70), larynx= 21 (SD 21), cutaneous= 10 (16), p=0.1).
The median overall survival (OS) for this cohort was 10.8 months (95% CI 8.5-13.1). Patients with high TILs had improved OS compared to patients with low TILs (12.9 (95% CI 5.1-20.6) vs 10.4 (95% CI 5.1-15.7) months, p=0.05 (Figure 1). This continued to be significant after controlling for HPV status on multivariate analysis (HR 1.9 (95% CI 1.1-3.3), p=0.02). For patients treated with ICIs as first line treatment for R/M disease (n=9), high TILs were associated with longer treatment duration versus low TILs (307.3 (SD 245.8) vs 50 (39.8) days, p=0.05).
Conclusions: HPV positive tumors are highly immune infiltrated tumors, even in the R/M setting. CD8+ TIL counts are independently associated with improved survival after controlling for HPV status. These data suggest that immune infiltration, as determined by CD8+ TILs, may serve as a predictive biomarker for treatment response to immunotherapy, however larger validation studies are needed.