Peripheral blood monocyte and T-lymphocyte activation levels at diagnosis predict long-term survival in head and neck squamous cell carcinoma patients HANS JØRGEN AARSTAD, 1,2 OLAV K. VINTERMYR, 3,1 ELLING ULVESTAD, 4,5 HELENE H. AARSTAD, 1 KENNETH W. KROSS 6 and JOHN. H. HEIMDAL 2,1 1 Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen; 2 Department of Otolaryngology/Head and Neck Surgery, Haukeland University Hospital, Bergen; 3 Department of Pathology, Haukeland University Hospital, Bergen; 4 Department of Microbiology, Haukeland University Hospital, Bergen; 5 Department of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway; and 6 Department of Otolaryngology/Head and Neck Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands Aarstad HJ, Vintermyr OK, Ulvestad E, Aarstad HH, Kross KW, Heimdal JH. Peripheral blood monocyte and T-lymphocyte activation levels at diagnosis predict long-term survival in head and neck squamous cell carcinoma patients. APMIS 2015; 123: 305–314. This study was performed to determine whether peripheral blood (PB) monocyte and/or lymphocyte activation at diag- nosis were associated with long-term prognosis in patients with head and neck squamous cell carcinoma (HNSCC), and to what extent such prognostic properties relate to human papilloma virus (HPV)-associated tumor infection of the included patients. This was a long-term prospective study describing patient survival in relation to PB T lymphocyte and monocyte activation in patients observed for up to 14 years following diagnosis. Sixty-four patients from a consec- utive cohort of newly diagnosed HNSCC patients along with 16 non-cancer control patients were included over a per- iod of almost 2 years. Monocyte responsiveness was assessed at diagnosis (N = 56 HNSCC/16 non-cancer controls) by measuring net levels of spontaneous vs lipopolysaccharide-induced monocyte chemotactic protein (MCP)-1 secretion in vitro. PB T lymphocyte activation was determined (N = 58 HNSCC/16 controls) by measuring the percentage of T cells expressing CD69 by flow cytometry. Whether HPV infection or not was determined by PCR analysis on formalin fixed paraffin-embedded tumor tissue. Tumor HPV-positive patients had better prognosis than HPV-negative patients. A low net MCP-1 response in monocytes predicted increased survival (Relative risk (RR) = 2.1; Confidence interval (CI): 1.1– 4.0; p < 0.05). A low percentage of CD69 positive T lymphocytes also predicted better prognosis (RR = 2.6; CI: 1.3– 5.0; p = 0.005). The predictive power of MCP-1 monocyte and CD69 T lymphocyte measures were retained when adjusted for age and gender of the patients and shown to be independent of each other (N = 50 HNSCC/16 controls). The results were similar in HPV tumor-positive and -negative patients. Patients with high monocyte- and/or T lympho- cyte activation status had low survival with 8% 5 year overall survival (OS) compared to 65% 5 year OS for patients with dual low activation levels (RR = 0.27; CI: 0.14–0.56; p < 0.001), mostly secondary to disease-specific survival. Both tumor HPV-positive and -negative HNSCC patients with high percentage of CD69 positive T lymphocytes and/or high monocyte MCP-1 secretion had low long-term survival. The data suggest that the general inflammatory and adap- tive immune systems are independently linked to the clinical aggressiveness of both tumor HPV-negative and -positive HNSCC patients. Key words: Head and neck cancer; neoplasms; immunology; monocyte; T lymphocyte; prognosis. Hans Jørgen Aarstad, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, N-5020 Bergen, Norway. e-mail: hans.aarstad@k1.uib.no Both epidemiological and experimental evidence sug- gest a close link between chronic infectious inflammation and the establishment and progression of some malignancies, including head and neck squa- mous cell carcinomas (HNSCC) (1–3). Recent evi- dence suggests that human papilloma virus (HPV) may cause HNSCC, and that such carcinomas have become more common during the last two decades (4). Received 17 April 2014. Accepted 23 November 2014 305 APMIS 123: 305–314 © 2015 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12356