title: Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer.
abstract: OBJECTIVE
  We evaluated the utility of chimeric γc homeostatic cytokine, IL-7/IL-7Rα-Fc, to restore host APC (antigen presenting cell) and T cell activities in lung cancer.
  
  
  METHODS
  Utilizing murine lung cancer models we determined the antitumor efficacy of IL-7/IL-7Rα-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFNγ were carried out to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7Rα-Fc in comparison to controls.
  
  
  RESULTS
  IL-7/IL-7Rα-Fc administration inhibited tumor growth and increased survival in lung cancer. Accompanying the tumor growth inhibition were increases in APC and T cell activities. In comparison to controls, IL-7/IL-7Rα-Fc treatment of tumor bearing mice led to increased: (i) levels of CXCL9, CXCL10, IFNγ, IL-12 but reduced IL-10 and TGFβ, (ii) tumor macrophage infiltrates characteristic of M1 phenotype with increased IL-12, iNOS but reduced IL-10 and arginase, (iii) frequencies of T and NK cells, (iv) T cell activation markers CXCR3, CD69 and CD127(low), (v) effector memory T cells, and (vi) T cell cytolytic activity against parental tumor cells. IL-7/IL-7Rα-Fc treatment abrogated the tumor induced reduction in splenic functional APC activity to T responder cells. The CXCR3 ligands played an important role in IL-7/IL-7Rα-Fc-mediated antitumor activity. Neutralization of CXCL9, CXCL10, or IFNγ reduced CXCR3 expressing activated T cells infiltrating the tumor and abrogated IL-7/IL-7Rα-Fc-mediated tumor growth inhibition.
  
  
  CONCLUSIONS
  Our findings show that IL-7/IL-7Rα-Fc promotes afferent and efferent antitumor responses in lung cancer.
authors.affiliation: Department of Medicine, UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA , California, USA.
authors.forename: Asa
authors.initials: A
authors.lastname: Andersson
authors.forename: Minu K
authors.initials: MK
authors.lastname: Srivastava
authors.forename: Marni
authors.initials: M
authors.lastname: Harris-White
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054370:Chemokine CXCL9 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015851:Interleukin-7 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D054367:Receptors, CXCR3 / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D007141:Immunoglobulin Fc Fragments; D015851:Interleukin-7; D054367:Receptors, CXCR3; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D007371:Interferon-gamma