Abstract

The proposal is to investigate the function of the NKG2D immunoreceptor in immune responses to tumor cells. NKG2D is a stimulatory receptor expressed by all natural killer (NK) cells, all activated cytotoxic T cells (CTL), all activated macrophages, and fractions of gamma/delta T cells and NK1.1+ T cells. NKG2D recognizes several related cell surface proteins (ligands), including Rael and H60. Expression of high levels of NKG2D ligands by target cells results in a strong attack by NK cells and activated macrophages, and an enhanced response of CTL to tumor-specific antigens. Most normal cells do not express these NKG2D ligands. Most tumor cell lines, in contrast, upregulate Rael and other NKG2D ligands. The hypothesis to be tested is that NKG2D and its ligands represent a system for tumor immunosurveillance. That is, it is proposed that NKG2D ligands are normally upregulated in developing tumor cells as a means to alert and activate the immune system, and that the resulting immune response serves to limit the development and/or growth of tumors in normal animals. This hypothesis will be tested using several approaches. In addition, preliminary experiments demonstrate that tumor cell lines transduced to express high levels of NKG2D ligands, when irradiated, function as potent therapeutic cancer vaccines that stimulate an effective immune response against established tumors of the same type (but not transduced). Therefore, studies will be undertaken to establish how effective this approach is and whether it can be effectively combined with other immunotherapies.
Specific Aim 1 : To determine the role of NKG2D isoforms associated with different adapter molecules in stimulating and costimulating NKG2D+ cells.
Specific Aim 2 : To generate and characterize gone targeted mice lacking NKG2D expression.
Specific Aim 3 : To assess the importance of NKG2D in surveillance of tumors in vivo.
Specific Aim 4 : To determine the efficacy of NKG2D stimulation as a cancer immunotherapy

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA093678-01A1
Application #
6575797
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2002-12-31
Project End
2007-11-30
Budget Start
2002-12-31
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$267,844
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Thompson, Thornton W; Jackson, Benjamin T; Li, P Jonathan et al. (2018) Tumor-derived CSF-1 induces the NKG2D ligand RAE-1? on tumor-infiltrating macrophages. Elife 7:
Hsu, Joy; Hodgins, Jonathan J; Marathe, Malvika et al. (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest 128:4654-4668
Kerdiles, Yann M; Almeida, Francisca F; Thompson, Thornton et al. (2017) Natural-Killer-like B Cells Display the Phenotypic and Functional Characteristics of Conventional B Cells. Immunity 47:199-200
Campbell, Amanda R; Duggan, Megan C; Suarez-Kelly, Lorena P et al. (2017) MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions. Cancer Immunol Res 5:778-789
Vance, Russell E; Eichberg, Michael J; Portnoy, Daniel A et al. (2017) Listening to each other: Infectious disease and cancer immunology. Sci Immunol 2:
Thompson, Thornton W; Kim, Alexander Byungsuk; Li, P Jonathan et al. (2017) Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. Elife 6:
Raulet, David H; Marcus, Assaf; Coscoy, Laurent (2017) Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells. Immunol Rev 280:93-101
Spiegel, Asaf; Brooks, Mary W; Houshyar, Samin et al. (2016) Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells. Cancer Discov 6:630-49
Iannello, Alexandre; Thompson, Thornton W; Ardolino, Michele et al. (2016) Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr Opin Immunol 38:52-8
Deng, Weiwen; Gowen, Benjamin G; Zhang, Li et al. (2015) Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348:136-9

Showing the most recent 10 out of 29 publications