miR-155 augments CD8(+) T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gamma(c) cytokines
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SCOPUS
- Title
- miR-155 augments CD8(+) T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic gamma(c) cytokines
- Authors
- Ji, Yun; Wrzesinski, Claudia; Yu, Zhiya; Hu, Jinhui; Gautam, Sanjivan; Hawk, Nga V.; Telford, William G.; Palmer, Douglas C.; Franco, Zulmarie; Sukumar, Madhusudhanan; Roychoudhuri, Rahul; Clever, David; Klebanoff, Christopher A.; Surh, CD; Waldmann, Thomas A.; Restifo, Nicholas P.; Gattinoni, Luca
- Date Issued
- 2015-01-13
- Publisher
- National Academy of Sciences
- 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 gamma c 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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/36272
- DOI
- 10.1073/PNAS.1422916112
- ISSN
- 0027-8424
- Article Type
- Article
- Citation
- Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 2, page. 476 - 481, 2015-01-13
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