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

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. CD274was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274mutation/deletion and TNFRSF14mutation (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/TNFRSF14genetic abnormalities than those without these changes. Both CD274and TNFRSF14genetic changes were significantly associated with Hashimoto’s thyroiditis (p= 0.01, p= 0.04, respectively), and CD274mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p= 0.0001). In conclusion, CD274/TNFRSF14inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.