title: Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.
abstract: The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.
authors.affiliation: Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
authors.forename: Kris
authors.initials: K
authors.lastname: Van Moer
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pierson
authors.forename: Piotr
authors.initials: P
authors.lastname: Przanowski
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Buart
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D015687:Cell Hypoxia / Q000276:immunology; D045744:Cell Line, Tumor; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025801:Ubiquitin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C099718:SQSTM1 protein, human; D050796:STAT3 Transcription Factor; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D019061:src-Family Kinases; D046988:Proteasome Endopeptidase Complex