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. 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-1 T cells may be more exhausted than PD-1 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 ( = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1 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-1 CD8 TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence ( < 0.001), while higher fractions of PD-1 T cells associated with HPV positivity and better outcome. In a murine HPV HNC model, anti-PD-1 mAb therapy differentially modulated PD-1 populations, and tumor rejection associated with loss of dysfunctional PD-1 CD8 T cells and a significant increase in PD-1 TIL. Thus, the extent of PD-1 expression on CD8 TIL provides a potential biomarker for anti-PD-1-based immunotherapy. .