Loss of heterozygosity, a frequent but a non‐exclusive mechanism responsible for HLA dysregulation in non‐Hodgkin's lymphomas

Abstract

Summary The frequent alteration of human leucocyte antigen (HLA) class I molecule expression observed in non‐Hodgkin's lymphomas (NHL), similarly to solid tumours, has been reported to favour tumoral escape from the immune system. In order to identify the underlying mechanisms, we analysed 15 HLA defective NHL including partial (n = 10) and total class I (n = 5) loss, as well as HLA class II defects (n = 5). The HLA defect concerned HLA‐A and ‐B antigens in 14 of 15 cases. In the cases with partial defect, the use of specific allelic monoclonal antibodies detected a defect of both alleles of A or B loci in six of seven tested cases. Allelic reverse transcription polymerase chain reaction (RT‐PCR) demonstrated defects in six of nine cases, including four alterations of both A and B mRNA alleles. Real‐time quantitative RT‐PCR (RQ‐PCR) did not detect the HLA‐DR transcript in the two negative HLA‐DR lymphomas, contrasting with the presence of CMH II transactivator (CIITA) transcript. Loss of heterozygosity (LOH) was detected in nine of 14 cases through variable pattern of nine microsatellites markers of the HLA locus. Taken together, these findings demonstrate the complexity and the variability of the mechanisms underlying HLA protein deficiencies with a high frequency of LOH. The diversity of these mechanisms indicates the importance of positive selection of HLA altered clones in the development of these NHL cases.

Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome

“…33,34 The 6p region also contains the genes coding for the human leukocyte antigens, which can be down-regulated in lymphoma cells via copy-neutral LOH. 35 Further studies are needed to understand the potential role of the specific patterns of 6q deletion and 6p gain and their relation to the microenvironment involved in the pathogenesis of MZLs, especially of MALT lymphoma. It is worth mentioning that, different from other lymphoma subtypes, 3,31,32 copy-neutral LOH did not appear to be a common event in MZLs.…”

Ly49 Receptors: Innate and Adaptive Immune Paradigms

“…Lost or aberrant surface expression of MHC-I in human tumors is classified into seven phenotypes as follows: (1) total HLA loss, (2) HLA haplotype loss, (3) HLA locus loss, (4) HLA allelic loss, (5) compound phenotypes, (6) unresponsiveness to interferons (IFNs), and (7) gain of MHC-Ib (63). Altered MHC-I expression is highly prevalent in human tumors and various alterations have been associated with different cancer types: HLA haplotype loss is the most common alteration and has been described in laryngeal (64), non-Hodgkin’s lymphoma (65), and pancreatic cancer (66). Loss of MHC-I expression along with up-regulation of ligands for activating NK cell receptors on tumor cells results in their recognition and elimination by NK cells.…”

Partial plasma cell differentiation as a mechanism of lost major histocompatibility complex class II expression in diffuse large B-cell lymphoma

“…6 Loss of MHC II protein expression has been documented in a variety of B-cell neoplasms and is associated with an aggressive clinical course. [11][12][13][14][15][16][17] MHC II loss has been associated with poor survival, independent of clinical prognostic variables, in DLBCLs treated with various regimens, 18,19 including MACOP-B therapy, 20 CHOP therapy, 6,21-23 risk-adapted therapy, 24 and R-CHOP therapy, 25 as well as in CHOP-treated PMBCLs. 26,27 In addition to lost expression, aberrant cytoplasmic protein expression of MHC II has been documented in Hodgkin lymphoma, and when grouped with true MHC II(Ϫ) cases, correlated with reduced survival.…”