2004 Fiscal Year Final Research Report Summary
Molecular mechanisms for tumor recognition and destruction by NK cells.
| Project/Area Number |
13214096
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Review Section |
Biological Sciences
|
|---|
| Research Institution | Juntendo University |
|---|
Principal Investigator |
YAGITA Hideo Juntendo University, School of Medicine, Associate Professor, 医学部, 助教授 (30182306)
|
|---|
| Project Period (FY) |
2001 – 2004
|
| Keywords | NK cells / tumor / immune surveillance / TRAIL / DR5 / TWEAK / activating receptor / inhibitory receptor |
|---|
| Research Abstract |
(1) We have revealed that the anti-metastatic effect of a-GalCer, a specific activator of NKT cells, is not mediated by cytolytic activity of NKT cells but by IFN-γ, which secondarily activates NK cells to produce sustained IFN-γ. We have also revealed TRAIL and suppression of tumor angiogenesis as the IFN-γ-dependent anti-tumor effctor mechanisms.
(2) We have found that recognition of CD70 and CD80 on tumor cells by CD27 and CD28 on NK cells not only enhances NK cell-mediated tumor rejection but also induces tumor-specific CTL and Thl in an IFN-γ-dependent manner.
(3) We have revealed that TRAIL expressed on hepatic NK cells plays a critical role in suppression of tumor metastasis in the liver. We have also revealed that IFN-γ-dependent induction of TRAIL in NK cells is involved in the anti-metastatic effects of IL-12 and a-GalCer. We have further revealed that TRAIL plays a pivotal role in the NK cell-mediated and IFN-γ-Tdependent immune surveilance against methylcholanthrene-ihduced or spontaneous tumor development in p53+/-mice.
(4) We have revealed that TWEAK, as well as TRAIL and TNF, contrbutes to tumor cell lysis by IFN-γ-adivated monocytes. We have also revealed that TWEAK induces caspase-dependent apoptosis and cathepsin B-dependent necrosis in some tumor cells via Fn14 but not via DR3.
(5) We have revealed that blastocyst MHC, a mouse homologue of HLA-G, can inhbi the NK cell-mediated rejection of TAP-deficient tumor cells by up-regulating the expression of Qa-1b, which engages CD94/NKG2A inhibitory receptor on NK cells.
(6) We have found that administration of an agonistic mAb against a death-inducing mouse TRAIL receptor (mDR5) not only induces regression of TRAIL-sensitive tumors but also elicits tumor-specific CTL that can also eradicate TRAIL-resistant variants.
|
