Abstract
Tumor immune escape plays a critical role in cancer, but the mechanisms involved in this process have still to be defined. In the recent years, progress has been made in understanding how peptides presented by MHC class I molecules were generated, in particular which proteases are involved in this process and how intracellular pathways influence antigen presentation in professional antigen-presenting cells and in various types of malignancies. Different MHC class I abnormalities have been found in solid tumors of distinct origin, but also in hematopoietic diseases. These include structural alterations such as total, haplotype and allelic loss of the MHC class I heavy chain, deletions and point mutations, in particular in β2-microglobulin and TAP1 as well as dysregulation of various components of the MHC class I antigen processing machinery (APM), which could occur at the epigenetic, transcriptional and posttranscriptional level. The lack or downmodulation of the expression of single or multiple components of the MHC class I antigen processing pathway may avoid the recognition of tumor cells by tumor-specific CD8+ cytotoxic T lymphocytes. This review will give an overview of the underlying molecular mechanisms of MHC class I abnormalities in human tumors of distinct histology, which also might have an impact on the design of T cell-based immunotherapies.
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Abbreviations
- Aa:
-
Amino acid
- APC:
-
Antigen-presenting cell
- APM:
-
Antigen processing machinery
- APN:
-
Aminopeptidase N
- BLH:
-
Bleomycin hydrolase
- β2-m:
-
β2-microglobulin
- LOH:
-
Loss of heterozygosity
- CSF:
-
Colony-stimulating factor
- CTL:
-
Cytotoxic T lymphocytes
- DAC:
-
2′5′Desoxyazacytidine
- DC:
-
Dendritic cells
- ER:
-
Endoplasmic reticulum
- ERAP:
-
ER aminopeptidase associated with antigen processing
- GM-CSF:
-
Granulocyte-macrophage colony stimulating factor
- HC:
-
Heavy chain
- HNSCC:
-
Head and neck squamous cell carcinoma
- IFN:
-
Interferon
- IL:
-
Interleukin
- LAP:
-
Leucin aminopeptidase
- LMP:
-
Low molecular weight proteins
- LOH:
-
Loss of heterozygosity
- Luc:
-
Luciferase
- MHC:
-
Major histocompatibility complex
- NK:
-
Natural killer
- PA:
-
Proteasome activator
- PDI:
-
Protein disulfide isomerase
- PLC:
-
Peptide loading complex
- RCC:
-
Renal cell carcinoma
- TAP:
-
Transporter associated with antigen processing
- TGF:
-
Transforming growth factor
- Tpn:
-
Tapasin
- TPPII:
-
Tripeptidyl peptidase II
- TSA:
-
Trichostatin A
- VPA:
-
Valproic acid
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Acknowledgments
This work was sponsored by the DFG projects (SE581/9-1, SE581/9-2, SE581/11-1). We would like to thank Anne Wasilewski for excellent secretarial help.
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This article is a symposium paper from the conference “Progress in Vaccination against Cancer 2007 (PIVAC 7)”, held in Stockholm, Sweden, on 10 and 11 September 2007.
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Seliger, B. Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother 57, 1719–1726 (2008). https://doi.org/10.1007/s00262-008-0515-4
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DOI: https://doi.org/10.1007/s00262-008-0515-4