IMMUNE-PRIVILEGED FIELD(S): LOOKING LOCAL RECURRENCE AND SECOND PRIMARY TUMORS IN HEAD AND NECK CANCER FROM A DIFFERENT VIEWPOINT  Stergios Doumas, Alexander Kolokotronis Dental School, Aristotle University of Thessaloniki, Thessaloniki, Greece Introduction: Head and neck cancer represents the 8th most common cause of cancer-related deaths worldwide. Local recurrence and second primary tumors account for the majority of deaths.”Field cancerization” and “second field tumor” were coined in an effort to explain these calamities (1). Head and neck cancer develops through the so-called linear progression model. Circulating tumor cells are being traced only in N+ patients, especially when extracapsular spread co-exists. Concurrently, peripheral blood T cell perturbations seem to increase with advanced disease. On the other hand, the establishment of tumor-driven immunosuppressive network during malignant progression is now appreciated (2). Developing tumors do not need to create tolerance systematically-local immune privilege will suffice. The key first step, however, is local suppression of tumor-specific immune responses (3). Materials-Methods: Interplay between an early lesion (premalignant or even a chronic inflammation) and its draining lymph node(s) results in the foundation of a local tolerance state both in the primary site and the DLNs, prior to node metastasis (Fig 1) (4). It is also known that suppression is encountered in metastasized nodes as well as in adjacent nodes (Fig2). In addition, recent SLNB studies in oral and oropharyngeal squamous cell carcinomas revealed that: a) tumors (especially midline, even T1) drain bilaterally, b) some tumors drain outside the “traditional” lymph node basin (5). It seems that factors such as chemokines (CCR7-CCL19 and CCL21, plus CXCL13- CXCR5 interactions, respectively) and VEGF-C play a singificant role in lympagiogenesis, apart from the mechanistic model of lymp flow. Also, HPV-positive oropharyngeal cancer, while metastasizing early, have better prognosis, and even if multiple primaries occur, there is lack of field cancerization. These properties may be due to specific genetic alterations and tropism seen in this particular group, but robust immune response against this virally-induced tumor has a major contribution (6). Hypothesis: We hypothesize that DLNs immunosuppression renders areas in continuity to primary tumor or seemingly distant, but with shared DLNs, unable to relay “danger” signals and generate immune reponse. These locales are more vulnerable to a local recurrence or second tumor, as they appear to be immune-privileged. Figure 2. Several immune system cell types and cytokines play major role in tumor-induced immunosuppression. TAMs, plasmacytoid DCs, immature/tolerogenic DCs, Treg subsets, TGF-β, IL-10. However, CD8+ CTL and CD20+ B- cells seem to confer a favorable outcome. Inset: nTreg immunosuppressive mechanisms in tumor microenvironment References Braakhuis BJ, Brakenhoff RH, Leemans CR. Second field tumors: a new opportunity for cancer prevention? Oncologist. 2005; 10(7):493-500. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008; 27(45):5904-12. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol. 2008; 8(1):74-80. Muller AJ, Sharma MD, Chandler PR et al. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci U S A. 2008; 105(44):17073-8. Stoeckli SJ. Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the head and neck. Laryngoscope. 2007; 117(9):1539-51. Rajjoub S, Basha SR, Einhorn E, Cohen MC, et al. Prognostic significance of tumor-infiltrating lymphocytes in oropharyngeal cancer. Ear Nose Throat J. 2007; 86(8):506-11. Figure 1. Interplay between a premalignant lesion and its DLN(s). Epithelia that drain to the common immunosuppressed DLNs are unable to generate a robust immune response