Innate immunity

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Expansion of Human Invariant Nkt Cells Ex Vivo Augments th2 Polarization and Anti-tumor Cytotoxicity

Wednesday, June 14
6:15 PM - 7:45 PM

Invariant natural killer T (iNKT) cells are potent innate immune mediators of immune regulation and tumor immunosurveillance. Key obstacles to the translation of human iNKT immunotherapy include the lack of dependable protocols for robust expansion of human iNKT cells and the requisite data on post-expanded iNKT cell phenotypes necessary for clinical application. We have developed a robust human peripheral blood CD3+Va24+Vb11+ iNKT cell expansion platform and defined a method to simultaneously augment both Th2 polarization and anti-tumor cytotoxicity of expanded human iNKT cells. Expanding from 2 x 108 starting PBMC, the cumulative 21-day mean increase in absolute number iNKT cells was 1750-fold (N = 41 random donor expansions). The CD4+ iNKT subset was preferentially expanded and was CD56negCD161+ and CD45RO+CD45RAneg, reflecting maturation and memory phenotypes. Cytokine gene and protein profiling showed an augmented Th2 cytokine profile (IL-4, IL-5, IL-13) in expanded iNKT cells following stimulation with anti-CD2/CD3/CD28 antibodies. Anti-CD2/CD3/CD28 stimulation enhanced expression of cytotoxic effector molecules including granzyme B in expanded iNKT cells. Direct cytotoxicity assays using 51Cr-loaded targets and unstimulated expanded iNKT cell effectors revealed a-galactosylceramide (a-GalCer)-dependent killing of the T-ALL line Jurkat. Anti-CD2/CD3/CD28-stimulated iNKT cell effectors killed Jurkat cells in an a-GalCer-independent manner. These data demonstrate a robust protocol to expand and novel pathways to augment cytokine secretion and cytotoxicity in iNKT cells from human peripheral blood. The functional studies suggest that expanded iNKT cells have the potential to impact not only cancer immunotherapy but also could impact the field of auto-immunity, vaccine augmentation, and anti-infective therapeutics.

Kelly Andrews

Research Laboratory Supervisor, Departments of Pediatrics and Microbiology and Immunology
University of Miami, Miller School of Medicine

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    Geoffrey Neale

    Director, Hartwell Center for Bioinformatics and Biotechnology
    St. Jude Children’s Research Hospital

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      Katherine Verbist

      Senior Research Technologist, Department of Oncology
      St. Jude Children’s Research Hospital

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        Paige Tedrick

        Research Technologist, Department of Oncology
        St. Jude Children’s Research Hospital

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          Kim E. Nichols

          Member, Department of Oncology
          St. Jude Children’s Research Hospital

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            Shalini Pereira

            Laboratory Director
            Scisco Genetics Inc

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              Daniel E. Geraghty

              Member, Clinical Research Division
              Fred Hutchinson Cancer Research Center

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                Asha B. Pillai

                Associate Professor, Departments of Pediatrics and Microbiology and Immunology
                University of Miami Miller School of Medicine

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                  Expansion of Human Invariant Nkt Cells Ex Vivo Augments th2 Polarization and Anti-tumor Cytotoxicity



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