Abstract：
:Destruction of cancer cells by cytotoxic T lymphocytes depends on immunogenic tumor peptides generated by proteasomes and presented by human leukocyte antigen (HLA) molecules. Functional differences arising from alleles of immunoproteasome subunits have not been recognized so far. We analyzed the genetic polymorphism of the immunoproteasome subunits LMP2 and LMP7 and of the transporters associated with antigen processing (TAP1 and TAP2) in two independently collected panels of colorectal carcinoma patients (N(1) = 112, N(2) = 62; controls, N = 165). High risk of colon cancer was associated with the LMP7-K/Q genotype (OR = 8.10, P = 1.10 × 10(-11)) and low risk with the LMP7-Q/Q genotype (OR = 0.10, P = 5.97 × 10(-13)). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-γ stimulation of colon carcinoma cell lines (N = 10), followed by analyses of mRNA expression of HLA class I, TAP1, TAP2, and LMP7, with real-time PCR. Whereas induction of HLA-B, TAP1, and TAP2 was comparable in all cell lines, transcript amounts of LMP7-Q increased 10-fold, but of LMP7-K only 3.8-fold. This correlated with a reduced transcript stability of LMP7-K (t(1/2) ≈ 7 minutes) compared with LMP7-Q (t(1/2) ≈ 33 minutes). In addition, LMP7-Q/Q colon carcinoma cells increased (the peptide based) HLA class I surface expression significantly after IFN-γ stimulation, whereas LMP7-Q/K and LMP7-K/K carcinoma cells showed minimal (<20%) changes. These results suggest that the presence of LMP7-K can reduce the formation of immunoproteasomes and thus peptide processing, followed by reduced peptide-HLA presentation, a crucial factor in the immune response against cancer.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Fellerhoff B,Gu S,Laumbacher B,Nerlich AG,Weiss EH,Glas J,Kopp R,Johnson JP,Wank Rdoi
10.1158/0008-5472.CAN-10-1883subject
Has Abstractpub_date
2011-12-01 00:00:00pages
7145-54issue
23eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-1883journal_volume
71pub_type
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