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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (22), p.6353-6364
• Main Authors: Kansy, Benjamin A, Concha-Benavente, Fernando, Srivastava, Raghvendra M, Jie, Hyun-Bae, Shayan, Gulidanna, Lei, Yu, Moskovitz, Jessica, Moy, Jennifer, Li, Jing, Brandau, Sven, Lang, Stephan, Schmitt, Nicole C, Freeman, Gordon J, Gooding, William E, Clump, David A, Ferris, Robert L
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antitumor activity; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; Discordance; Disease Models, Animal; Disease-Free Survival; Exhaustion; Gene Expression - drug effects; Head & neck cancer; Head and Neck Neoplasms - complications; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Human papillomavirus; Humans; Immune checkpoint; Immunotherapy; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mice, Inbred C57BL; Monoclonal antibodies; Outcome Assessment (Health Care) - methods; Outcome Assessment (Health Care) - statistics & numerical data; Papillomavirus Infections - complications; Papillomavirus Infections - drug therapy; Papillomavirus Infections - immunology; PD-1 protein; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Proportional Hazards Models; Tumor-infiltrating lymphocytes; γ-Interferon
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-3167

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. .