Combined Genetic Inactivation of β2-Microglobulin and CD58 Reveals Frequent Escape from Immune Recognition in Diffuse Large B Cell Lymphoma

Abstract

SUMMARY We report that diffuse large B-cell lymphoma (DLBCL) commonly fails to express cell-surface molecules necessary for the recognition of tumor cells by immune-effector cells. In 29% of cases, mutations and deletions inactivate the β2-microglobulin gene, thus preventing the cell-surface expression of the HLA class-I (HLA-I) complex that is necessary for recognition by CD8+ cytotoxic T-cells. In 21% of cases, analogous lesions involve the CD58 gene, which encodes a molecule involved in T and natural killer cell-mediated responses. In addition to gene inactivation, alternative mechanisms lead to aberrant expression of HLA-I and CD58 in >60% of DLBCL. These two events are significantly associated in this disease, suggesting that they are co-selected during lymphomagenesis for their combined role in escape from immune-surveillance.

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

“…[6][7][8] Other recurrent lesions can be found in all the DLBCL subtypes, including inactivation of histone and/or chromatin modifying genes CREBBP, EP300, and MLL2 9,10 and of genes involved in immune recognition, such as b2-microglobulin and CD58. 11 It is likely that additional, undescribed genetic defects may also contribute to the pathogenesis of DLBCL.…”

“…[6][7][8] Other recurrent lesions can be found in all the DLBCL subtypes, including inactivation of histone and/or chromatin modifying genes CREBBP, EP300, and MLL2 9,10 and of genes involved in immune recognition, such as b2-microglobulin and CD58. 11 It is likely that additional, undescribed genetic defects may also contribute to the pathogenesis of DLBCL.In the present study, aimed to identify new recurrent genetic defects in DLBCL, we performed genomic profiling analysis on 166 DLBCL samples, which enabled us to characterize a new recurrent lesion on chromosome 11q24.3 occurring in up to onequarter of cases. The region contains 2 ETS transcription factors, ETS1 and FLI1.…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Such evolved tumor cells carry massive genetic alterations and are therefore able to suppress all steps of immune action, namely, the recruitment of, engagement by and function of cytolytic cells. [59][60][61][62] Additional tumor-extrinsic criteria, such as the genotype of the patient, can also impact the clinical outcome. Efficacy of the treatment in the relapsing follicular lymphoma patients was expected to result from the enhancement of ADCC by rituximab/ BrHPP/IL-2 co-administration.…”

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

“…In B-NHL, genetic and epigenetic alterations create tumor phenotypes that are protected against immune cytolysis. [1][2][3][4][5][6][7] Immune escape also evolves through the concerted upregulation of gene expression. 8 For example, the B-NHL subtypes FL and DLBCL upregulate the expression of genes involved in the PD1/PDL1-2 axis, the CTLA4 ligand axis, the biosynthesis of immunosuppressive Galectin 3, and the genes IDO1, VEGFA, PGE2, IL10, and HGF, among several others.…”