Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 61, Issue 9, Pages 1359-1371Publisher
SPRINGER
DOI: 10.1007/s00262-012-1321-6
Keywords
HLA class I; beta 2 microglobulin; Microsatellite instability; Human leukocyte antigen; Tumor immune escape; Loss of heterozygosity
Categories
Funding
- Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III
- Red Genomica del Cancer [RETICRD 06/020]
- Consejeria de Salud de la Junta de Andalucia
- Consejeria de Innovacion
- Ciencia y Empresa Junta de Andalucia [P08-TIC-4299]
- Direccion General de Investigacion y Gestion del Plan Nacional I + D + i [TIN2009-13489]
- Proyecto de Investigacion de Excelencia [CTS-3952, CVI-4740, P06/-CTS-02200]
- Plan Andaluz de Investigacion (PAI, Group CTS) in Spain
- European Searchable Tumour Cell Line Database (ESTDAB) [QLRI-CT-2001-01325]
- European Network [LSHC-CT-2004-503306]
- Cancer Immunotherapy project [OJ 2004/c158, 18234]
- Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF) Alliance on Immunotherapy of Cancer
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Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8(+) cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, beta 2-microglobulin (beta 2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that beta 2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single beta 2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of beta 2m loss in both tumor types. It also summarizes recent studies that point to an acquired beta 2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy.
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