Characterization of human lymphocyte antigen class I antigen-processing machinery defects in renal cell carcinoma lesions with special emphasis on transporter-associated with antigen-processing down-regulation.
The HLA class I antigen-processing machinery (APM) plays a crucial role in the generation of peptides from endogenously synthesized proteins and in their presentation to cytotoxic T lymphocytes. The potential role of defects of APM components in immune escape mechanisms used by malignant cells has prompted us to analyze their expression in renal cell carcinoma (RCC) lesions with special emphasis on TAP because of its critical role in the loading of HLA class I antigens with peptides. Immunohistochemical staining of 51 formalin-fixed RCC lesions and autologous normal renal epithelium detected transporter associated with antigen processing (TAP)1 and tapasin deficiencies in 63 and 80% of the tumor lesions. Impaired low molecular weight protein (LMP)2 and LMP7 expression was found in 73 and 33% of the RCC lesions analyzed, respectively. In contrast to the high frequency of APM component down-regulation, HLA class I heavy chain and beta(2)-microglobulin defects were detected in only 12 and 10% of the lesions, respectively. Concomitant TAP1 and LMP2 deficiencies were found in approximately 57% of RCC lesions, whereas a coordinated down-regulation of all APM components occurred only in 5% of the tumor specimens analyzed. The presence of APM defects was independent of tumor stage and grade but varied significantly among the RCC subtypes. TAP abnormalities do not appear to be attributable to structural alterations because no mutations in TAP1 were detected in TAP1-deficient RCC lesions. These data suggest that TAP defects in RCC lesions are caused by regulatory abnormalities. Therefore, T-cell-based immunotherapy may benefit from the administration of cytokines that up-regulate TAP expression.
Seliger
Barbara
B
Johannes Gutenberg-University, 3rd Department of Internal Medicine, D-55101 Mainz, Germany. B.Seliger@3-med.klinik.uni-mainz.de
Atkins
Derek
D
Bock
Michaela
M
Ritz
Ulrike
U
Ferrone
Soldano
S
Huber
Christoph
C
Störkel
Stefan
S
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017951:Antigen Presentation; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D001613:beta 2-Microglobulin / Q000378:metabolism
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; C073119:TAP1 protein, human; D001613:beta 2-Microglobulin; C071313:LMP-2 protein; C071692:TAP2 protein, human; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex