High numbers of tumour‐infiltrating activated cytotoxic T lymphocytes, and frequent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis

Abstract

Loss of both HLA class I and class II expression in B cell lymphomas is a mechanism of escape from a cytotoxic T lymphocyte (CTL) immune response and will therefore give a strong selective survival advantage in tumours expressing strong immunogenic antigens. We investigated loss of HLA expression using specific antibodies on tissue sections from 254 B cell lymphomas originating from nodal and different extranodal sites in relation to numbers of tumour-infiltrating T cells. Complete loss of HLA class I and II was observed in a minority of the nodal, stomach, and skin lymphomas but in the majority of the lymphomas originating from the testis and the CNS. Interestingly, relatively high percentages of activated CTLs were detected in both primary testicular and CNS lymphomas compared to lymphomas at other sites, with highest percentages in the testis (p < 0.0001). We conclude that loss of both HLA class I and II expression occurs very frequently in lymphomas originating from the testis and the CNS as compared to nodal and some other extranodal sites. The presence of high percentages of activated CTLs in the testicular and CNS lymphomas suggests that loss of HLA expression provides a strong growth advantage for lymphoma cells in these immune-privileged sites.

Mechanisms and Effects of Loss of Human Leukocyte Antigen Class II Expression in Immune-Privileged Site-Associated B-Cell Lymphoma

“…In both IP-DLBCL subtypes, small homozygous deletions affected the HLA-DR and HLA-DQ genes, whereas larger hemizygous deletions affected the whole MHC region, including class I and III regions, as well. The specificity of this down-regulation in testicular DLBCL was confirmed in a recent immunohistochemical study on a large series of primary extranodal DLBCL presenting at various sites (7). In another recent study on predominantly primary nodal (non-IP) DLBCL, Rimsza et al (8) showed that loss of expression of HLA class II is highly discriminative for the clinical behavior of the disease and by far the most significant single prognostic factor.…”

Primary lymphoma of the central nervous system: just DLBCL or not?

“…The frequently observed loss of HLA-DQ, HLA-DR, and HLA-A due to homozygous or heterozygous 6p21.3 deletion (Table S1) may facilitate tumor-cell survival in organs characterized by a physiologically down-regulated immunophenotype. [27][28][29] Such loss of the HLA region has been suggested to be a prerequisite of lymphomas of immunoprivileged organs contributing to escape from the immune response. [27][28][29] In this regard, the observation of a patient with PCNSL and testicular relapse 8 years thereafter is of note; while both tumors carried identical IG gene rearrangements, the progressive loss of HLA expression on the tumor cells may have facilitated immune escape.…”

“…[27][28][29] Such loss of the HLA region has been suggested to be a prerequisite of lymphomas of immunoprivileged organs contributing to escape from the immune response. [27][28][29] In this regard, the observation of a patient with PCNSL and testicular relapse 8 years thereafter is of note; while both tumors carried identical IG gene rearrangements, the progressive loss of HLA expression on the tumor cells may have facilitated immune escape. 30 A further unexplained issue relates to the preferential usage of the IGHV4-34 gene segment in PCNSL.…”

From brain to testis: immune escape and clonal selection in a B cell lymphoma with selective out-growth in two immune sanctuariesy

“…This is substantiated by high numbers of infiltrating cytotoxic T cells in PCNSL and testicular DLBCL at the moment of clinical diagnosis. 6 In the case presented here, this infiltrate is more pronounced in the testicular relapse than in the CNS localisation. Under pressure of this immune reaction the ongoing remodelling of the idiotype, in addition to progressive loss of HLA class II and HLA class I expression, might thus provide escape mechanisms for the tumour cells, necessary for their sustained survival and growth at these sites.…”

“…3 A common aberration leading to immune escape of PCNSL and testicular DLBCL is loss of HLA expression. 4,5,6 Another common feature of both lymphoma types is a high level of (often ongoing) somatic hypermutation (SHM) in the immunoglobulin heavy chain (IgH) genes. 1,7,8 Although usually presenting with stage IE disease, patients with PCNSL or testicular DLBCL have a poor prognosis that has only recently improved upon introduction of novel chemotherapy strategies.…”