PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

TLDR

Expression of immune checkpoint receptors on tumor‑infiltrating lymphocytes may enable more effective immunotherapy in head and neck cancer. The study hypothesizes that the level of PD‑1 expression on CD8+ T cells better predicts T‑cell function, prognosis, and response to anti‑PD‑1 therapy in head and neck cancer. In a murine HPV+ head and neck cancer model, anti‑PD‑1 antibody treatment reduced dysfunctional PD‑1high CD8+ T cells and increased PD‑1low TILs, correlating with tumor rejection. Higher frequencies of PD‑1high CD8+ TILs predict poorer disease‑free survival and are associated with HPV‑negative status, whereas PD‑1low TILs correlate with HPV positivity and better outcomes, supporting PD‑1 expression level as a biomarker for anti‑PD‑1 therapy. Published in Cancer Research, vol.

Abstract

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. ©2017 AACR.