Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites

Abstract

In B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8+ and CD4+ cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P < .01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P < .01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P < .001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

“…PCR‐SSP that we used for HLA genotyping is used in pretransplant diagnostics at our hospital and has been employed in other studies of tumor origin in PTLD . Decreased expression of HLA‐A, ‐B and ‐DR antigens on tumor cells caused by genetic deletions or transcriptional disruption has been reported as an important immune escape mechanism in DLBCL in immunocompetent individuals but has not been observed in DLBCL posttransplant . Thus, this phenomenon would not affect the ability to determine donor or recipient origin of PTLD by PCR‐SSP in this study.…”

Diffuse large B‐cell lymphoma in immunoprivileged sites: association of vitreoretinal, testicular and central nervous system lymphoma

“…So far it is not certain whether PVRL and PCNSL represent multiple manifestations of one entity or whether they are distinct disorders, one originating in the eye(s) and the other in the brain. The central nervous system (CNS), eyes and testes are immune‐privileged sites and have been considered to represent sites where lymphoma cells might escape from T lymphocyte‐mediated immunosurveillance and where chemotherapy might have reduced efficacy (Riemersma et al. 2000).…”

“…2010). It was hypothesized that in immune privileged sites, the malignant cells can escape the immunosurveillance and thereby the destruction initiated by the immune system as well as from chemotherapy (Riemersma et al. 2000).…”

Primary central nervous system diffuse large B‐cell lymphoma has poorer immune cell infiltration and prognosis than its peripheral counterpart

“…Through the presentation to T cells by self MHC molecules, this Id antigen could be potentially recognized as a target by the host immune system. The expression of major histocompatibility complex (MHC) molecules in DLBCL cells can be a surrogate marker for lymphoma‐specific antigens . Dendritic cells are the most potent antigen‐presenting cells.…”

“…In non‐CNS DLBCL, the composition of infiltrating immune cells correlates with patient survival, but similar studies performed on cases of PCNSL are sparse . The CNS is an immune‐privileged sanctuary where immune recruitment may not be as efficient as in other locations, and this may result in cancer progression.…”