Involvement of the chaperone tapasin in HLA-B44 allelic losses in colorectal tumors

Abstract

Tumors can exhibit selective allelic losses of HLA class I antigens as part of altered HLA phenotypes. In colorectal tumors, the HLA class I allele most frequently lost is HLA-B44, although the precise mechanism responsible for this loss has not been described to date. From a total of 95 colorectal cryopreserved tumor samples, we selected (by immunohistochemical staining) 13 tumors with HLA-B44-negative expression. Loss of heterozygosity at 6p21.3 was demonstrated to be the cause of the negative expression in 4 cases. In the remaining 9 cases, structural analyses of microdissected tissue samples of the 3 subtypes of HLA-B44 loss in these tumors (B*4402, B*4403 and B*4405) did not reveal any mutations. However, all 3 subtypes of HLA-B44 presented in this study shared a common characteristic: the presence of an aspartic amino acid residue at position 114 in the HLA class I heavy chain. This residue has been described as determining tapasin dependence for the surface expression of these alleles and therefore for antigen presentation. We studied tapasin transcription by RT-PCR in these tumors and found tapasin downregulation in all 9 tumors samples with the HLA-B44-negative phenotype. In contrast, tapasin was normally transcribed in HLA-B44-positive colorectal tumors samples, as well as in 3 HLA-B44-negative laryngeal carcinomas and 1 bladder tumor. Defective tapasin transcription seems to be an alteration responsible for the absence of HLA-B44 expression in colorectal tumors, thus contributing to the generation of tumor immune escape phenotypes.

TAP1 and TAP2 Polymorphisms and Their Linkage Disequilibrium With HLA-DR, -DP, and -DQ in an Eastern Andalusian Population

“…Therefore, only the MHC class I molecules exhibit significant genetic polymorphisms in the PLC. These polymorphisms can functionally alter the tapasin-mediated interaction with TAP, thereby modulating the incorporation of a given MHC class I allele into the PLC [45]. The expression level of polymorphic MHC class I molecules can also be modulated by viral proteins that interfere with PLC components (e.g., tapasin and TAP) to impair antigen presentation [29].…”

TAPBPR Promotes Antigen Loading on MHC-I Molecules Using a Peptide Trap

“…Collectively, these processes ensure the correct folding, trafficking and prolonged cell surface display of pMHC-I antigens (9). Improper chaperone function is associated with severe impairment of the adaptive immune system and results in accelerated disease progression in the context of autoimmunity, cancer and pathogen infection (10–17).…”

The Double Role of the Endoplasmic Reticulum Chaperone Tapasin in Peptide Optimization of HLA Class I Molecules

“…In addition, the role of tapasin in the peptide optimization is supported by the finding that certain HLA class I alleles differ in tapasin dependence for the HLA class I surface expression. The HLA class I tapasin‐independent alleles are expressed in the cell surface in the absence of tapasin [56] in contrast to tapasin‐dependent alleles that are not expressed [57]. For example, the HLA‐B*2705 allele is tapasin independent [56], in contrast to HLA‐B*4402, which is highly dependent on tapasin [57].…”