LOH at 6p21.3 region and HLA class altered phenotypes in bladder carcinomas

Abstract

Alterations in HLA class I antigen expression have been frequently described in different epithelial tumors and are thought to favor tumor immune escape from T lymphocyte recognition. Multiple molecular mechanisms are responsible for these altered HLA class I tumor phenotypes. Some are structural defects that produce unresponsiveness to treatment with interferons. Others include alterations in regulatory mechanisms that can be switched on by treatment of tumor cells with different cytokines. One important mechanism belonging to the first group is loss of heterozygosity (LOH) at chromosome region 6p21.3, which can lead to HLA haplotype loss. In this investigation, the frequency of LOH at 6p21 chromosome region was studied in 69 bladder carcinomas. Short tandem repeat analysis showed that 35% of cases had LOH in this chromosome region. By considering these results together with immunohistological findings previously published by our group, we identified a distribution pattern of HLA class I altered phenotypes in bladder cancer. The most frequently altered phenotype in bladder carcinomas was total loss of HLA class I expression (17 cases, 25%), followed by phenotype II associated with HLA haplotype loss (12 cases, 17.5%), and HLA allelic loss (ten cases, 14.5%). Nine cases (13%) were classified as having a compound phenotype, five cases (7%) as having HLA locus loss, and in 16 cases (23%) no alteration in HLA expression was detected. An important conclusion of this report is that a combination of different molecular and immunohistological techniques is required to precisely define which HLA alleles are lost during tumor progression and to characterize the underlying mechanisms of these losses. These studies should be performed when a cancer patient is to be included in an immunotherapy protocol that aims to stimulate different immune effector mechanisms.

Inhibition of STAT3 activity re-activates anti-tumor immunity but fails to restore the immunogenicity of tumor cells in a B-cell lymphoma model

“…29 Loss of HLA class I expression is common in cancer cells and appears to be one of the major strategies used by cancer cells to evade host immunosurveillance. [30][31][32] Several mechanisms such as abnormal signal transduction, epigenetic modifications, and gene structural alterations are responsible for the loss of the HLA class I antigen. 33 In the case of TA2 lymphomabearing mice, the loss of MHC class I molecules was caused by a missense mutation in the β2M gene.…”

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.…”

Clinical Applications of Natural Killer Cells

“…However, with the arrival of other techniques, such as studies of microsatellites to detect the loss of heterozygosity (LOH) on chromosome 6, it has been shown that LOH (haplotype loss) is the most frequent alteration of HLA class I expression [139,[141][142][143][144]. This alteration is caused by various defects in the HLA genomic region (i.e., the short arm of chromosome 6, 6p21), including chromosomal dysfunction, mitotic recombination, and genetic conversion.…”