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Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):476-81. doi: 10.1073/pnas.1422916112. Epub 2014 Dec 29.

miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines.

Author information

1
Experimental Transplantation and Immunology Branch and tawald@helix.nih.gov jiyun@mail.nih.gov gattinol@mail.nih.gov.
2
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
3
Experimental Transplantation and Immunology Branch and.
4
Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, 790-784, Korea; and.
5
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.

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.

KEYWORDS:

adoptive immunotherapy; homeostatic cytokines; lymphodepletion; microRNA-155

PMID:
25548153
PMCID:
PMC4299215
DOI:
10.1073/pnas.1422916112
[Indexed for MEDLINE]
Free PMC Article

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