MHC class I-related antigen-processing machinery component defects in feline mammary carcinoma (original) (raw)
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International Journal of Oncology, 2004
Malignant transformation of breast epithelia is frequently associated with an altered expression of MHC products and of antigen processing molecular machinery. The consequent impairment of tumor immune recognition is thought to confer to tumor cells a selective advantage with respect to survival and metastatization. In order to understand if metastatic breast cancer lesions might be associated with a defective proteasome subunit expression that, in turn, might limit the peptide availability and prevent stable cell surface HLA class I-tumor antigen expression, we studied by immunostaining the expression of B2-microglobulin, HLA class I antigens and proteasome subunits LMP-2 and LMP-10 in 35 matched primary and metastatic human breast carcinoma lesions. Overall, we found a downregulation of LMP-2 in 51.4% of the lesions, of LPM-10 in 45.7% of the lesions, of HLA class I heavy chain in 40.0% of the lesions, while 62-microglobulin was downregulated in 25.7% of the lesions studied. In most primary and metastatic lesions the downmodulation of each antigen examined was coordinated. In the cases where a selective downmodulation of antigens was observed in the primary or in the metastatic lesion (with the exception of 62-microglobulin), it was rather observed in the primary lesions. However, LMP-10 showed a significant selective downmodulation in the metastases as well. Antigen downmodulation does not appear therefore to represent a strategy for the primary tumor to metastasize successfully.
JNCI Journal of the National Cancer Institute, 2013
The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to all CD8 + T-cell adaptive immune responses, including those against tumors. The generation of peptides and their loading on MHC class I molecules is a multistep process involving multiple molecular species that constitute the so-called antigen processing and presenting machinery (APM). The majority of class I peptides begin as proteasome degradation products of cytosolic proteins. Once transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing), peptides are not bound randomly by class I molecules but are chosen by length and sequence, with peptidases editing the raw peptide pool. Aberrations in APM genes and proteins have frequently been observed in human tumors and found to correlate with relevant clinical variables, including tumor grade, tumor stage, disease recurrence, and survival. These findings support the idea that APM defects are immune escape mechanisms that disrupt the tumor cells' ability to be recognized and killed by tumor antigen-specific cytotoxic CD8 + T cells. Detailed knowledge of APM is crucial for the optimization of T cell-based immunotherapy protocols.
International Journal of Cancer, 2003
Previous reports from our group indicated that the MHC class I phenotype of metastatic lung colonies produced by a mouse fibrosarcoma tumor clone (B9) were, depending on the immune status of the host, MHC class I negative in immunocompetent mice and MHC class I positive in immunodeficient athymic nude/nude mice. Now we report the identification of the molecular alterations responsible for the changes of MHC class I molecules in both situations. Metastatic nodes were analyzed for the mRNA level of H-2 class I and β2-microglobulin genes, and several gene components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM). These included the genes coding for the low-molecular-weight proteins LMP2, LMP7, LMP10, the transporter associated with antigen processing (TAP-1, TAP-2), and calnexin, calreticulin, tapasin, PA-28-α, PA-28-β, ERP-59 and ER-60. Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice. In contrast, similar techniques with mRNA preparations obtained from metastatic nodes from immunodeficient mice showed that the mRNA expression level of these genes was highly positive. Interestingly, the MHC class I-positive or negative phenotypes of the metastatic colonies correlated with in vivo immunogenicity. H-2 positive metastasis grew more slowly than the H-2 negative ones when injected intrafootpat in syngeneic immunocompetent animals and were finally rejected. These results provide evidence of the role of T cells in immune surveillance against tumors and identify a mechanism targeted by antitumor T lymphocytes to generate MHC class I-negative tumor escape variants. © 2003 Wiley-Liss, Inc.
Journal of Biological Chemistry, 2000
The proteasome plays a crucial role in the proteolytic processing of antigens presented to T cells in the context of MHC class I molecules. However, the rules governing the specificity of cleavage sites are still largely unknown. We have previously shown that a CTL-defined antigenic peptide derived from the MAGE-3 tumor associated antigen (MAGE-3 271-279 , FLWGPRALV in one-letter code) is not presented at the surface of melanoma cell lines expressing the MAGE-3 protein. Using purified proteasome and MAGE-3 271-279 peptides extended at C-terminus by 6 amino acids, we had identified predominant cleavages after residues 278 and 280 but no detectable cleavage after residue Val 279 , the C-terminus of the antigenic peptide. In the present study, we have investigated the influence of Pro 275 , Leu 278 and Glu 280 on the proteasomal digestion of MAGE-3 271-285 substituted at these positions. We show that positions 278 and 280 are major proteasomal cleavage sites because they tolerate most amino acid substitutions. In contrast, the peptide bond after Val 279 is a minor cleavage site, influenced by both distal and proximal amino acid residues.
Neoplasia, 2007
In human tumors, changes in the surface expression and/ or function of major histocompatibility complex (MHC) class I antigens are frequently found and may provide malignant cells with a mechanism to escape control of the immune system. This altered human lymphocyte antigen (HLA) class I phenotype can be caused by either structural alterations or dysregulation of genes encoding subunits of HLA class I antigens and/or components of the MHC class I antigen-processing machinery (APM). Herein we analyze the expression of several proteins involved in the generation of MHC class I epitopes in feline injection site sarcoma, a spontaneously occurring tumor in cats that is an informative model for the study of tumor biology in other species, including humans. Eighteen surgically removed primary fibrosarcoma lesions were analyzed, and an enhanced expression of two catalytic subunits of immunoproteasomes, PA28 and leucine aminopeptidase, was found in tumors compared to matched normal tissues. As a functional counterpart of these changes in protein levels, proteasomal activities were increased in tissue extracts from fibrosarcomas. Taken together, these results suggest that alterations in the APM system may account for reduced processing of selected tumor antigens and may potentially provide neoplastic fibroblasts with a mechanism for escape from T-cell recognition and destruction. Neoplasia (2007) 9, 960 -969
The role of the proteasome activator PA28 in MHC class I antigen processing
Molecular Immunology, 2002
The proteasome system is the major source for the generation of viral antigens and tumor antigens presented by major histocompatibility complex class I (MHC class I) molecules. A specific feature of the proteasomal antigen processing machinery is that five of its components are inducible by IFN-␥. Two of these are the ␣ and  subunits of the proteasome activator PA28. Our results show that PA28 selectively up-regulates the presentation of viral MHC class I epitopes and that down regulation PA28 in tumor cells results in impaired presentation of a human TRP2 tumor antigen.