IB-01 GLIOMA-DERIVED GALECTIN-1 IS A POTENT SUPPRESSOR OF NK IMMUNOSURVEILLANCE

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2014-11, Vol.16 (suppl 5), p.v107-v107
• Main Authors: Baker, G., Chockley, P., Yadav, V., Doherty, R., Ritt, M., Sivaramakrishnan, S., Castro, M., Lowenstein, P.
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou257.1

Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immunosurveillance. However, the mechanisms used by malignant brain tumors to subvert this innate immune function remain unclear. We show that shRNA-mediated knockdown of the beta -galactoside-binding lectin, galectin-1 (gal-1), in malignant glioma cells leads to the failure to form lethal intracranial tumors in RAG1-/- mice, a mouse strain devoid of adaptive immunity. However, gal-1 deficient glioma growth is fully restored on implantation into the brain of severely immunocompromised NOD-scid IL2Rg null mice, which lack both adaptive and innate immune function, thus implicating the innate immune response in the early rejection of gal-1 deficient glioma. Immunodepletion of NK cells in RAG1-/- or C57BL/6J mice using anti-asialo GM1 or anti-NK1.1 antibodies permit the growth of large gal-1 deficient gliomas. Antigen-specific IFN- gamma ELISpot assays using splenocytes from immunocompetent C57BL/6J mice indicate that gal-1 deficient glioma is cleared prior to the onset of an adaptive anti-tumor immune response. Flow cytometric analysis of brain tumor-infiltrating immune cells reveal that gal-1 deficient gliomas contain significantly more granzyme B+ NK cells compared to gal-1 expressing gliomas. In-vitro experiments further show that gal-1 deficient glioma cells are over three times more sensitive to NK-mediated tumor lysis. We conclude that glioma-derived gal-1 is a powerful inhibitor of NK-mediated cytotoxicity in-vivo, and predict that its suppression will be of therapeutic value in the treatment of human malignant brain tumors by dramatically heightening anti-tumor NK immunosurveillance.