Distribution of HLA class I altered phenotypes in colorectal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21

Abstract

HLA class I loss or down-regulation is a widespread mechanism used by tumor cells to avoid tumor recognition by cytotoxic T lymphocytes, and thus favor tumor immune escape. Multiple mechanisms are responsible for these HLA class I alterations. In different epithelial tumors, loss of heterozygosity (LOH) at chromosome region 6p21.3, leading to HLA haplotype loss, occurs in 6-50% of all cases depending on the tumor entity. In this paper we report the frequency of LOH at 6p21 in 95 colorectal carcinomas (CRC) previously analyzed for altered HLA class I expression with immunohistological techniques. We used PCR microsatellite amplification of selected STR markers located on Chromosome 6 to identify LOH with DNA from microdissected tumor tissues and the surrounding stroma. Sequence-specific oligonucleotide analysis was performed in microdissected stroma and tumor cells for HLA typing, and to detect HLA haplotype loss. A high frequency (40%) of HLA haplotype loss was found in CRC. Eight tumors showed microsatellite instability. We sometimes observed two or more mechanisms responsible for HLA alteration within the same HLA-altered phenotype, such as LOH and HLA class I total loss. In 25 tumors (26%) no HLA class I alteration could be identified. These data are potentially relevant for CRC patients undergoing T-cell-based immunotherapy.

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response

“…In this context, our group has frequently detected human carcinomas with HLA phenotype I that also present one HLA haplotype loss, 8,15 indicating a similar accumulative process to that observed in the Ando xenograft model. At early stages, specific autologous immune response can select tumor cells with one HLA haplotype loss 11,35 that are then immune-tolerant.…”

“…No HLA class II expression was found in Ando-2 cell line. LOH on 6p21.3 is an irreversible event and the most frequent mechanism for HLA class I alterations in colorectal, 8 laryngeal 14 and bladder carcinomas, 15 and it has also been detected in melanoma cell lines. 16 HLA haplotype loss can induce tumor evasion of CD81 CTL-mediated immune attacks because CTLs can eliminate tumor cells expressing HLA class I molecules in a complex with immunodominant tumor peptides.…”

“…7 HLA class I-negative tumor cells with HLA haplotype loss are a frequent finding in human tumors. 8 It has been proposed that the immune response against cancer sculpt, the immunogenic phenotype of tumors that develop in an immunocompetent host. 9 Tumor progression and metastatic spread has been related to progressive loss of HLA expression on cancer cells, associated with more aggressive tumor growth.…”

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

“…62). In some studies, the proximal border of the LOH region was identified as being situated directly within FRA6H.…”

Infiltration of Lynch Colorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

“…Such immune reaction will act as a vector of selective pressure that favors the outgrowth of tumor clones that acquired immune evasive phenotypes. Multiple mechanisms have been shown to underlie defects in HLA class I expression by tumor cells; they include mutations in the individual HLA class I genes, HLA-A, -B, and -C, located on chromosome 6p21.3 (9); loss of heterozygosity at 6p21.3 (10); mutations in b2-microglobulin (b2M; ref. 11), the molecular chaperone required for the cell surface expression of HLA class I antigens; and defects in components of the HLA class I-associated antigen-processing machinery (12,13).…”