Copy Neutral LOH Affecting the Entire Chromosome 6 Is a Frequent Mechanism of HLA Class I Alterations in Cancer

SIMPLE SUMMARY: Loss of antigen presentation due to the altered expression of tumor HLA class I (HLA-I) molecules is a common mechanism of cancer immune escape. Loss of HLA-I haplotype, locus or a single allele due to genetic and chromosomal aberrations, may result in reduced antigen presentation and, thus, facilitate immune evasion. Here, we demonstrate the prevalence of the copy neutral loss of heterozygosity (CN-LOH) involving HLA-I heavy chain and B2M gene in various human tumor cell lines and tissues. We discuss the impact of the LOH in HLA genes on tumor immune rejection, clonal expansion and association with the cancer recurrence in the immunotherapy settings. It represents a genetic barrier for effective treatment and can be considered as a potential genetic biomarker of cancer immune escape. ABSTRACT: 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.