title: Chronically stimulated mouse invariant NKT cell lines have a preserved capacity to enhance protection against experimental tumor metastases.
abstract: In pre-clinical models, CD1d restricted invariant Natural Killer T (iNKT) cells play a pivotal role in natural anti-tumor immune responses, mainly by trans-activating cells of both the innate and adaptive arms via swift and potent cytokine secretion. We have previously reported that patients with a severely reduced circulating iNKT cell pool have a poor clinical response to radio therapy of head and neck squamous cell carcinoma. Therefore, these patients might benefit from an immunotherapeutic approach aimed at the increase of circulating levels of iNKT cells. Furthermore, we have generated both human and mouse iNKT cell lines, and demonstrated that they had retained the capacity to release both Th1 and Th2 type cytokines even after long-term in vitro expansion using alpha-galactosylceramide (alphaGalCer) pulsed dendritic cells (DC). Here, we establish, in a pre-clinical tumor model that the large scale long lived polyclonal iNKT cell lines we generated have a preserved capacity to evoke an in vivo cytokine storm upon adoptive transfer, independently of supplemental alphaGalCer administration. This results in an augmented NK cell mediated protection against B16.F10 experimental lung metastases in vivo. These findings underscore the potential of autologous adoptive transfer of ex vivo expanded iNKT cells as a strategy to enhance immunotherapeutic modalities for the treatment of cancer patients.
authors.affiliation: Cancer Center Amsterdam, VUMC Institute for Cancer and Immunology (V-ICI), Division of Immune Therapy, Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Molling
authors.forename: María
authors.initials: M
authors.lastname: Moreno
authors.forename: Jan
authors.initials: J
authors.lastname: de Groot
authors.forename: Hans J J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Hetty J
authors.initials: HJ
authors.lastname: Bontkes
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary*; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines