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Down-regulation of the transporter for antigen presentation, proteasome subunits, and class I major
1Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Abstract:
Tumor cells may alter the expression of proteins involved in antigen processing and presentation, allowing them to avoid recognition and elimination by cytotoxic T cells. In this study, reverse transcription-PCR was used to assess the expression in human tumor cell lines of mRNA for multiple components of the class I MHC antigen-processing pathway, including several proteasome subunits that have been implicated in antigen processing but have not been previously examined in this context (e.g., low molecular weight polypeptide proteasome subunit (LMP) 10, proteasome activator (PA) 28alpha, and PA28beta). Deficiencies in the expression of antigen-processing genes were demonstrated in 9 of 27 cell lines, representing a variety of histological types. In some cases, virtually complete deficiencies were observed in the expression of the four genes encoded within the MHC (TAP1, TAP2, LMP2, and LMP7), as well as LMP10, which is encoded outside the MHC. Combined deficiencies of these gene products were common, and marked deficiency of LMP10 was found in five of the nine cell lines with deficits. The existence of deficiencies in the expression of genes at dispersed loci suggested that the basis for the deficiencies was a regulatory mechanism, as opposed to mutation or deletion of these genes. Furthermore, most of the deficiencies were reversed by treatment with IFN-gamma. In contrast to such extreme deficiencies, we found unaltered or only partially decreased expression of PA28alpha and PA28beta in tumor cell lines. Thus, tumors may evade immune surveillance by simultaneously down-regulating multiple components of the MHC-I antigen-processing pathway, thereby altering the processing and presentation of tumor antigens. Expression of essential proteasome subunits, however, may still be maintained.
Insights
Tumor cells evade immune detection by down-regulating antigen processing genes, particularly LMP10. Interferon-gamma treatment often reversed these deficiencies, suggesting a regulatory mechanism for immune evasion.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Tumor cells can evade cytotoxic T cell recognition by altering antigen processing and presentation.
- The class I MHC antigen-processing pathway is crucial for presenting tumor antigens to T cells.
Purpose of the Study:
- To investigate the expression of antigen-processing pathway components in human tumor cell lines.
- To identify deficiencies in genes involved in MHC class I antigen processing and their potential role in immune evasion.
Main Methods:
- Reverse transcription-PCR was used to analyze mRNA expression of multiple class I MHC pathway components.
- Assessed expression of proteasome subunits like LMP10, PA28alpha, and PA28beta.
- Examined the effect of Interferon-gamma (IFN-gamma) on gene expression.
Main Results:
- Deficiencies in antigen-processing genes were found in 9 of 27 tumor cell lines.
- Complete deficiencies in MHC-encoded genes (TAP1, TAP2, LMP2, LMP7) and LMP10 were observed.
- LMP10 deficiency was common, and most deficiencies were reversed by IFN-gamma treatment.
- PA28alpha and PA28beta expression remained largely unaltered.
Conclusions:
- Tumors may evade immune surveillance by down-regulating multiple MHC class I antigen-processing pathway components.
- Deficiencies appear to be regulated rather than caused by mutation or deletion.
- Essential proteasome subunit expression may be maintained despite pathway deficiencies.