P02.27.B INTRATUMORAL EXPRESSION OF THE HYPOXIA-INDUCIBLE FACTOR 1 PATHWAY AND IMMUNE EVASION IN CHORDOMA

Abstract BACKGROUND Chordoma is a rare, malignant tumor of the skull base and spine known for its propensity for recurrence, its resistance to chemoradiotherapy and the shortened patient survival. The tumor immune microenvironment of chordoma is characterized by a hypoxic tumor cell parenchyma separated into lobules by fibro-vascular septa where abundant clusters of immune cells are found, a pattern suggestive of immune evasion. MATERIAL AND METHODS To investigate whether the cellular location of hypoxia-inducible factor (HIF)-1α and HIF-1-regulated carbonic anhydrase 9 (CA9) supports the notion of immunosuppression in human chordoma, we evaluated their immunoexpression in clival and spinal chordoma specimens and in chordoma cell lines. RESULTS We observed strong immunoreactivity for HIF-1α and CA9 in the majority of cases studied. HIF-1α expression was detected in tumor cell nuclei (40/45 cases, 89%) whereas no nuclear HIF-1α immunoreactivity was seen in inflammatory cells. Expression of CA9 showed an intense membranous pattern of immunoreactivity in tumor cells (30/36 cases, 83%) but no immunoreactivity in inflammatory cells. CD8+ T lymphocytes and FoxP3+ regulatory CD4 T cells (22/31 cases, 71%) were scattered in the septa while not observed in the tumor cell lobules. Consistent with these results, primary chordoma cells grown under normoxic or hypoxic (1% O2) conditions exhibited baseline expression of HIF-1α and CA9 under normoxia, which was enhanced in response to hypoxia as shown by Western blot. CONCLUSION Our findings support the hypothesis that most chordomas demonstrate tumoral expression of the hypoxia-regulated HIF-1 pathway that could exert immunosuppressive effects on chordoma-associated inflammatory cells and/or tumor cells. (Supported by the Bergman Family Foundation)