title: Invariant natural killer T cells regulate anti-tumor immunity by controlling the population of dendritic cells in tumor and draining lymph nodes.
abstract: BACKGROUND
  Invariant natural killer T (iNKT) cells are CD1d-restricted T cells, which respond rapidly to antigen recognition and promote development of anti-tumor immunity in many tumor models. Surprisingly, we previously found that mice deficient in iNKT cells developed spontaneous CD8(+) T cells responses partially effective at inhibiting metastases in mice bearing the 4T1 mammary carcinoma, and showed a markedly improved response to treatment with local radiotherapy and anti-CTLA-4 antibody compared to wild type (WT) mice.
  
  
  METHODS
  To understand the mechanisms of the immunosuppressive function of iNKT cells, dendritic cells (DCs) were analyzed by immunohistochemistry and flow cytometry in WT and iNKT-deficient (iNKT(-/-)) mice. The effects of antibody-mediated blockade of CD1d on DC number and phenotype, priming of anti-tumor T cells, and tumor response to treatment with local radiotherapy and anti-CTLA-4 antibody were evaluated. To determine if the improved response to treatment in the absence of iNKT cells was independent from the immunotherapy employed, 4T1-tumor bearing WT and iNKT(-/-) mice were treated with local radiotherapy in combination with antibody-mediated CD137 co-stimulation.
  
  
  RESULTS
  DCs in 4T1 tumors and tumor-draining lymph nodes but not distant lymph nodes were significantly reduced in WT mice compared to iNKT(-/-) mice (p < 0.05), suggesting the selective elimination of DCs cross-presenting tumor-associated antigens by iNKT cells. Consistently, priming of T cells to a tumor-specific CD8 T cell epitope in mice treated with radiotherapy and anti-CTLA-4 or anti-CD137 was markedly enhanced in iNKT(-/-) compared to WT mice. CD1d blockade restored the number of DC in WT mice, improved T cell priming in draining lymph nodes and significantly enhanced response to treatment.
  
  
  CONCLUSIONS
  Here we describe a novel mechanism of tumor immune escape mediated by iNKT cells that limit priming of anti-tumor T cells by controlling DC in tumors and draining lymph nodes. These results have important implications for the design of immunotherapies targeting iNKT cells.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016 USA.
authors.forename: Karsten A
authors.initials: KA
authors.lastname: Pilones
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016 USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Aryankalayil
authors.affiliation: Department of Radiology, New York University School of Medicine, New York, NY 10016 USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Babb
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016 USA ; Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016 USA ; New York University School of Medicine, Alexandria Center for Life Sciences, 450 East 29th St, Room 324B, New York, NY 10016 USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Demaria
keywords: Breast cancer; CD137; CD1d; CD8+ T-cells; CTLA-4; Dendritic cells; Immunoregulation; Invariant NKT cells; Radiotherapy