Immune Suppression and Colorectal Cancer

C. Evans; A. G. Dalgleish; D. Kumar

Disclosures

Aliment Pharmacol Ther. 2006;24(8):1163-1177. 

In This Article

Loss/downregulation of HLA Class I Antigen Processing and Presentation

Human leucocyte antigen class I antigens play a crucial role in the interaction of malignant cells with immune cells; presenting peptides derived from TAA to TAA-specific CTL and modulating the interaction between NK cells and T cells with tumour cells.[97] Alteration in HLA class I expression occur in many cancers and potentially plays a role in the clinical course of the disease by enabling tumour cells to escape T cell-mediated immune responses.[98] Their downregulation is the result of mutations in the HLA class I genes themselves, abnormalities in their regulation and/or defects in HLA class I-dependent antigen processing[99] with seven major altered HLA class I phenotypes identified.[100] Colorectal tumours show high levels of HLA class I alteration[101,102,103] through loss or mutations in β2-microglobulin genes, loss of HLA heavy chain genes, selective lack of expression of HLA alleles and regulatory defects in HLA expression including loss of expression of the peptide transporters associated with antigen processing.[104]

HLA class I antigen defects are associated with a poor clinical prognosis in a number of tumours including bladder carcinoma, prostate carcinoma, head and neck squamous cell carcinoma, melanoma and squamous cell carcinoma of the cervix.[97,105] However, there are conflicting reports concerning colorectal cancer with either none or even a positive correlation between disease-free survival and HLA class I loss.[103,106,107] The reason for this may reflect the fact that HLA-negative cells become more sensitive to NK activity which also has to be evaded before disease progression. These findings may also be attributed to differences in types of immune response elicited by the tumours or their different routes of metastasis.[97] The strength and quality of the host immune response determines the tumour escape phenotype[108] and immunoselective pressures lead to the outgrowth of cells with increasing defects of antigen presentation.[109] Colorectal cancers with microsatellite instability reflect this, being associated with increased tumour-infiltrating lymphocytes and an improved survival[110] whilst having significantly more frequent defects of HLA class I antigen processing and presentation.[109] It should also be noted that whilst HLA class I downregulation negates antigen presentation by the tumour, direct presentation of antigen by a tumour may be relatively unimportant with more significance placed upon the concept of 'cross priming' in which antigen-presenting cells (APC), such as DC and macrophages pick up antigen released by dead tumour cells and subsequently present them to T cells.[9]

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