期刊
BLOOD
卷 118, 期 4, 页码 992-1001出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-02-339135
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资金
- European Molecular Biology Organization
- Fundacao Calouste Gulbenkian SDH Oncologia [2008/99293]
- Italian Ministry of Health [ICH-2007643769]
- European Union [204188]
- Istituto Clinico Humanitas [20090917]
- European Research Council [StG260352]
- Fundacao para a Ciencia e Tecnologia [SFRH/BD/37898/2007]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/37898/2007] Funding Source: FCT
The success of cancer immunotherapy depends on productive tumor cell recognition by killer lymphocytes. gamma delta T cells are a population of innate-like lymphocytes endowed with strong, MHC-unrestricted cytotoxicity against tumor cells. This notwithstanding, we recently showed that a large proportion of human hematologic tumors is resistant to gamma delta peripheral blood lymphocytes (PBLs) activated with specific agonists to the highly prevalent V gamma 9V delta 2 TCR. Although this probably constitutes an important limitation to current gamma delta T cell-mediated immunotherapy strategies, we describe here the differentiation of a novel subset of V delta 2(-) V delta 1(+) PBLs expressing natural cytotoxicity receptors (NCRs) that directly mediate killing of leukemia cell lines and chronic lymphocytic leukemia patient neoplastic cells. We show that V delta 1(+) T cells can be selectively induced to express NKp30, NKp44 and NKp46, through a process that requires functional phosphatidylinositol 3-kinase (PI-3K)/AKT signaling on stimulation with gamma(c) cytokines and TCR agonists. The stable expression of NCRs is associated with high levels of granzyme B and enhanced cytotoxicity against lymphoid leukemia cells. Specific gain-of-function and loss-of-function experiments demonstrated that NKp30 makes the most important contribution to TCR-independent leukemia cell recognition. Thus, NKp30(+)V delta 1(+) T cells constitute a novel, inducible and specialized killer lymphocyte population with high potential for immunotherapy of human cancer. (Blood. 2011; 118(4): 992-1001)
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