title: Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma.
abstract: We studied the impact of natural killer T (NKT) cell activation by alpha-galactocysylceramide (α-GalCer, α-GC) on cancer cell repopulation during chemotherapy in murine mesothelioma. The number of NKT cells was found to be increased during the development of murine mesothelioma. NKT cells specifically recognize α-GC through CD1d resulting in their activation and expansion. Tumor-bearing mice were treated with chemotherapy once weekly, and α-GC was followed after each cycle of chemotherapy. Anti-tumor effect was evaluated on wild-type (WT) and CD1d knockout (CD1dKO) mice. Cancer cell proliferation and apoptosis were evaluated by Ki67 and TUNEL immunohistochemistry. CD4(+) and CD8(+) T cell proportion and activation in tumor, spleen, draining lymph node and peripheral blood were determined by flow cytometry, and gene expression of activated T cell-related cytokines was quantified by reverse transcription PCR. NKT cells were identified by CD1d-α-GC-tetramer staining. In WT mice, tumor growth delay was achieved by cisplatin (Cis), and this effect was improved in combination with α-GC, but α-GC alone had little effect. Cancer cell proliferation during chemotherapy was significantly inhibited by α-GC, while cancer cell death was significantly upregulated. α-GC following chemotherapy resulted in NKT cell expansion and an increase of interferon-γ production in the draining lymph node, blood and spleen. Gene expression of immune-associated cytokines was upregulated. Strikingly, the percentage of inducible T cell co-stimulator(+)CD4 T cells, Th17/Tc17 cells increased in splenocytes. In CD1d KO mice, however, Cis alone was less effective and Cis + α-GC provided no additional benefit over Cis alone. α-GC alone had minimal effect in both mice. NKT activation between cycles of chemotherapy could improve the outcome of mesothelioma treatment.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yun
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tagawa
authors.forename: Luis
authors.initials: L
authors.lastname: De la Maza
authors.forename: Matthew Onn
authors.initials: MO
authors.lastname: Wu
authors.forename: Julie
authors.initials: J
authors.lastname: Yu
authors.forename: Yidan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D005838:Genotype; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; D005699:Galactosylceramides