Thyroid MALT lymphoma: self-harm to gain potential T-cell help

Leukemia. 2021 Dec;35(12):3497-3508. doi: 10.1038/s41375-021-01289-z. Epub 2021 May 21.

Abstract

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases / genetics
  • Dioxygenases / metabolism
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Lymphoma, B-Cell, Marginal Zone / genetics
  • Lymphoma, B-Cell, Marginal Zone / immunology*
  • Lymphoma, B-Cell, Marginal Zone / metabolism
  • Lymphoma, B-Cell, Marginal Zone / pathology
  • Molecular Targeted Therapy
  • Mutation
  • Receptors, Tumor Necrosis Factor, Member 14 / genetics
  • Receptors, Tumor Necrosis Factor, Member 14 / immunology
  • T-Lymphocytes / immunology*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / immunology*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / immunology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • DNA-Binding Proteins
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human
  • Dioxygenases
  • TET2 protein, human
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3