title: Downregulation of endogenous STAT3 augments tumoricidal activity of interleukin 15 activated dendritic cell against lymphoma and leukemia via TRAIL.
abstract: Effector functions in tumor resistance by dendritic cells (DCs) are less well characterized. In this study, we describe that the murine DCs upon stimulation with recombinant IL-15 in vitro or in vivo, expresses TNF superfamily member TRAIL which mediates cytotoxicity and growth inhibition against a murine lymphoma called Dalton lymphoma (DL) via apoptosis. Presence of tumor lysate or intact tumor cells significantly reduces the DC mediated tumoricidal effect, possibly via masking and down-regulating TRAIL in DCs. The antitumor effect of DC derived TRAIL was further augmented by deactivation of STAT3 in tumor cells by cucurbitacin I, which makes it more susceptible to DC derived TRAIL Treatment of tumor cells with cucurbitacin I upregulates TRAIL receptor expression in addition to activation of caspases. Compared to naïve DCs, DCs from tumor bearing mice are significantly impaired in TRAIL expression and consequent antitumor functions against DL which was partially restored by activation with IL-15 or LPS. Priming with recombinant IL-15 prolongs the survival of tumor bearing mice treated with cucurbitacin I. Naïve peripheral blood DCs derived from chronic myeloid leukemia (CML) patients have significant impairment in expression of TRAIL and consequent tumoricidal properties against TRAIL sensitive lymphoma cell lines and primary tumor cells compared to normal control.
authors.affiliation: Immunobiology Laboratory, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Sumit Kumar
authors.initials: SK
authors.lastname: Hira
authors.affiliation: Department of Pathology, Burdwan Medical College, West Bengal 713104, India.
authors.forename: Indrani
authors.initials: I
authors.lastname: Mondal
authors.affiliation: Department of Pathology, Burdwan Medical College, West Bengal 713104, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Immunobiology Laboratory, Banaras Hindu University, Varanasi 221005, India. Electronic address: pp_manna@yahoo.com.
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Manna
mesh_terms: D000328:Adult; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D054728:Cucurbitacins / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D006801:Humans; D019409:Interleukin-15 / Q000008:administration & dosage / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D019409:Interleukin-15; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D054728:Cucurbitacins
keywords: Dendritic cell; IL-15; Lymphoma; STAT3; TRAIL