title: miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines.
abstract: Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic "cytokine sinks." These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8(+) T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.
authors.affiliation: Experimental Transplantation and Immunology Branch and tawald@helix.nih.gov jiyun@mail.nih.gov gattinol@mail.nih.gov.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzesinski
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Experimental Transplantation and Immunology Branch and.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Hu
authors.affiliation: Experimental Transplantation and Immunology Branch and.
authors.forename: Sanjivan
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Experimental Transplantation and Immunology Branch and.
authors.forename: Nga V
authors.initials: NV
authors.lastname: Hawk
authors.affiliation: Experimental Transplantation and Immunology Branch and.
authors.forename: William G
authors.initials: WG
authors.lastname: Telford
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Zulmarie
authors.initials: Z
authors.lastname: Franco
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, 790-784, Korea; and.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Surh
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 tawald@helix.nih.gov jiyun@mail.nih.gov gattinol@mail.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Experimental Transplantation and Immunology Branch and tawald@helix.nih.gov jiyun@mail.nih.gov gattinol@mail.nih.gov.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
mesh_terms: D000818:Animals; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D058951:gp100 Melanoma Antigen; D051057:Proto-Oncogene Proteins c-akt
keywords: adoptive immunotherapy; homeostatic cytokines; lymphodepletion; microRNA-155