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Low Levels of Circulating Invariant Natural Killer T Cells Predict Poor Clinical Outcome in Patients With Head and Neck Squamous Cell Carcinoma

Johan W. Molling, Jacqueline A.E. Langius, Johannes A. Langendijk, C. René Leemans, Hetty J. Bontkes, Hans J.J. van der Vliet, B. Mary E. von Blomberg, Rik J. Scheper, Alfons J.M. van den Eertwegh

From the Departments of Pathology, Medical Oncology, Nutrition and Dietetics, Otolaryngology/Head and Neck Surgery, and Internal Medicine, VU University Medical Center, Amsterdam; and Department of Radiotherapy, Groningen University Medical Center, Groningen, the Netherlands

Address reprint requests to A.J.M. van den Eertwegh, MD, PhD, Department of Medical Oncology, VU Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: vandeneertwegh{at}vumc.nl

Purpose: Evading antitumor immune responses is an important aspect of the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Invariant CD1d-restricted natural killer T (iNKT) cells play an allegedly pivotal role in such responses via transactivation of immune effector cells. It has been reported that iNKT cells are reduced in peripheral blood of cancer patients compared with healthy controls. Here, we investigated whether the extent of this deficiency affected disease outcome in HNSCC patients.

Patients and Methods: In a prospective study, circulating iNKT cell numbers were evaluated in 47 patients before radiotherapy. Patients were stratified in three groups based on iNKT cell levels, and clinical data were obtained during a median follow-up period of 31 months.

Results: A small, compared with an intermediate or large, circulating iNKT cell fraction was significantly associated with decreased 3-year overall survival rate (39% v 75% and 92%, respectively), disease-specific survival rate (43% v 87% and 92%, respectively), and locoregional control rate (31% v 74% and 92%, respectively) in HNSCC patients. Cox regression revealed that the iNKT cell level, as well as clinical T stage, was an independent prognostic parameter even after correction for the confounding effect of age.

Conclusion: A severe circulating iNKT cell deficiency was related to poor clinical outcome in HNSCC patients, suggesting their critical contribution to antitumor immune responses. Furthermore, screening for iNKT cell levels may be useful for determining which patients can benefit from immunotherapeutic adjuvant therapies aimed at reconstitution of the circulating iNKT cell pool.

Supported by Grant No. VU2002-2607 (B.M.E.v.B., R.J.S., and A.J.M.v.d.E.) from the Dutch Cancer Society and Grant No. 920-03-142 (H.J.J.v.d.V.) from the Netherlands Organization for Scientific Research.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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