Copy Neutral LOH Affecting the Entire Chromosome 6 Is a Frequent Mechanism of HLA Class I Alterations in Cancer
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AuthorGarrido, María Antonia; Ruiz-Cabello Osuna, Francisco; Garrido Torres-Puchol, Federico; Aptsiauri, Natalia
Cancer immune escapeHLA class ICopy-neutral loss of heterozygosity (CN-LOH)Antigen presentationBeta2-microglobulinCytotoxic T-cellsCancer immunotherapy
Garrido, M.A.; Perea, F.; Vilchez, J.R.; Rodríguez, T.; Anderson, P.; Garrido, F.; Ruiz-Cabello, F.; Aptsiauri, N. Copy Neutral LOH Affecting the Entire Chromosome 6 Is a Frequent Mechanism of HLA Class I Alterations in Cancer. Cancers 2021, 13, 5046. https://doi.org/10.3390/ cancers13205046
SponsorshipISCIII Research Institute co-financed by the European Union and Ministerio de Ciencia e Innovación (FEDER-Fondo Europeo de Desarrollo Regional and National Plan 2020, MICIN) (PI17/00197, PI18/00826, and PID2020-115087GB-100); Junta de Andalucía in Spain (Group CTS-143 and B-CTS-410-UGR-20); Consejería de Salud, Junta de Andalucía through the contract “Nicolás Monardes” [C-0013-2018]
Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides by cytotoxic T lymphocytes favoring cancer immune escape during natural tumor evolution. These alterations can be caused by genomic defects, such as loss of heterozygosity at chromosomes 6 and 15 (LOH-6 and LOH-15), where HLA class I genes are located. There is growing evidence indicating that LOH in HLA contributes to the immune selection of HLA loss variants and influences the resistance to immunotherapy. Nevertheless, the incidence and the mechanism of this chromosomal aberration involving HLA genes has not been systematically assessed in different types of tumors and often remains underestimated. Here, we used SNP arrays to investigate the incidence and patterns of LOH-6 and LOH-15 in a number of human cancer cell lines and tissues of different histological types. We observed that LOH in HLA is a common event in cancer samples with a prevalence of a copy neutral type of LOH (CN-LOH) that affects entire chromosome 6 or 15 and involves chromosomal duplications. LOH-6 was observed more often and was associated with homozygous HLA genotype and partial HLA loss of expression. We also discuss the immunologic and clinical implications of LOH in HLA on tumor clonal expansion and association with the cancer recurrence after treatment.