The peptides presented by the major histocompatibility complex (MHC) class I antigens are the primary targets on tumor cells for immune recognition by host cytotoxic T lymphocytes (CTL). A large proportion of tumors derived from MHC class I positive epithelia have total or selective loss of cell surface MHC class I expression. This may allow tumors to evade the immune recognition by avoiding MHC class I antigen presentation. While genetic mechanisms that lead to antigen presentation defects are largely unknown, it is clear that expression of multiple genes involved in antigen presentation such as those encode transporters for peptides across endoplasmic reticulum (ER) membrane (TAP-1 and TAP-2), proteosome components LMP-2 and LMP-7 are affected. We have recently characterized a recurrent tumor in mouse that had defective expression of TAP1/2 and LMP2/7. Expression cloning revealed that the defect could be complemented by overexpression of proto-oncogene PML-F12. Moreover, we have found that endogenous PML contains a dominant negative mutation. The main goal of the proposed study is to establish whether malfunction of PML is responsible for antigen presentation defects in murine and human tumors. We proposed to investigate the mechanisms by which PML controls multiple genes devoted to MHC class I antigen processing. Our proposed study is fundamental to understand the basic mechanism for tumor evasion of host anti-tumor immunity. Given expression of PML gene in normal tissue, it is likely the mechanism we have identified is involved in antigen presentation in normal tissue. As such, our study may establish PML as a master regulator controlling MHC class I antigen presentation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082355-03
Application #
6377341
Study Section
Experimental Immunology Study Section (EI)
Project Start
1999-08-06
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$218,797
Indirect Cost
Name
Ohio State University
Department
Pathology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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