title: IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity.
abstract: Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.
authors.affiliation: Department of Pediatrics and Department of Pathology and Immunology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Liu
authors.forename: Liping
authors.initials: L
authors.lastname: Song
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.forename: Amy N
authors.initials: AN
authors.lastname: Courtney
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Gao
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Marinova
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.forename: Andras
authors.initials: A
authors.lastname: Heczey
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: Eugene
authors.initials: E
authors.lastname: Kim
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
mesh_terms: D000293:Adolescent; D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; C569274:IL15 protein, human; D019409:Interleukin-15; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha