Down-Regulation of HLA Class I Antigen-Processing Molecules in Malignant Melanoma

Abstract

Expression of the proteasome subunits LMP2 and LMP7, the MHC-encoded transporter subunits TAP1 and TAP2, and HLA Class I antigens was examined by immunoperoxidase staining in 10 nevi and 98 melanoma lesions (60 primary and 38 metastatic), because these molecules play an important role in the presentation of melanoma-associated peptide antigens to cytotoxic T cells. LMP2 was less frequently expressed than LMP7 in primary and metastatic melanoma lesions. TAP1, TAP2, and HLA Class I antigen expression was more frequently (P < 0.05) down-regulated in metastatic than in primary melanoma lesions and in nevi. A synchronous TAP1, TAP2, and HLA Class I antigen down-regulation was observed in 58% of primary and 52% of metastatic lesions. TAP and HLA Class I antigen down-regulation in primary lesions was significantly associated with lesion thickness, stage of disease, reduced time to disease progression, and reduced survival. These results suggest that TAP down-regulation plays a role in the clinical course of malignant melanoma, probably by providing melanoma cells with a mechanism to escape from cytotoxic T lymphocyte recognition during disease progression.

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response

“…TAP1 down-regulation or loss has been reported in various tumor types at frequencies ranging from 10 to 84%. 6,23 APM defects have been identified in several types of human and mouse tumor, e.g., cervical cancer, 24 cutaneous melanoma, 25 breast cancer, 26 lung cancer, 27 colorectal carcinoma 28 and bladder carcinoma. 29 Down-regulation of APM components may or may not be associated with decreased transcription of HLA class I heavy chain and b2-microglobulin.…”

Serial killing of tumor cells by cytotoxic T cells redirected with a CD19‐/CD3‐bispecific single‐chain antibody construct

“…3 A frequent finding is the downregulation of expression or complete loss of HLA alleles on tumors. [4][5][6] Likewise, tumor cells can become deficient in peptide antigen delivery and processing through loss of TAP transporters, which are responsible for loading peptides onto MHC class I complexes in the ER 7 and by exchanging proteasome subunits. 8 Although certain vaccination approaches with tumor-associated peptides or proteins can induce tumor-specific T-cell responses in patients, the efficacy and response rate of such treatments is not very satisfactory and far from clinic routine.…”

Downregulation of HLA Class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma

“…As the anti-tumour cytotoxic T lymphocyte (CTL) response is induced by the recognition of immunogenic epitopes that are presented on various types of HLA class I molecules on the tumour (Marincola et al, 2000;Tangri et al, 2001;Cabrera et al, 2007;Nagorsen and Thiel, 2008), it is important to evaluate the status of HLA class I molecules on tumour cells. It has been reported that the downregulation of HLA class I molecules in the tumour commonly occurred, and the defect of HLA class I molecules is significantly related to patient survival in several malignancies including ESCC (Hosch et al, 1997a;Kageshita et al, 1999;Ryschich et al, 2005;Vitale et al, 2005;Ogino et al, 2006;Ramnath et al, 2006;Speetjens et al, 2008;Ueda et al, 2008). Moreover, it is well known that the downregulation of HLA class I on the tumour allows it to evade CTL-mediated anti-tumour immunity, leading to variant cancer cells that arise from the parent tumour during tumour progression at both primary and metastatic sites.…”