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

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. Ahigher 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-1(high) T cells may be more exhausted than PD-1(low) 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-1(high) CD8(+) TILs were more frequent in HPV+ patients and represented a more dysfunctional subset with compromised IFN-gamma secretion. Moreover, HNC patients with higher frequencies of PD-1(high) CD8(+) TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1(low) T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1(high)/(low) populations, and tumor rejection associated with loss of dysfunctional PD-1(high) CD8(+) T cells and a significant increase in PD-1(low) TIL. Thus, the extent of PD-1 expression on CD8(+) TIL provides a potential biomarker for anti-PD-1-based immunotherapy (C) 2017 AACR.