MYD88 L265P mutation promoted malignant B cell resistance against T cell-mediated cytotoxicity via upregulating the IL-10/STAT3 cascade

Abstract

The myeloid differentiation factor 88 (MYD88) signaling plays critical roles in the developments of B cells. Recent studies demonstrated that in the activated B cell subtype of diffuse large B cell lymphoma (DLBCL), approximately one-third of the patients harbored somatically acquired MyD88 L265P mutation in their lymphomas. It remains unclear whether B cell lymphomas with MYD88 L265P mutation respond differently toward CD8⁺ T cell-mediated cytotoxicity. Here, we demonstrated that, when incubated with autologous CD8⁺ T cells, the MYD88 L265P mutant lymphomas were more resistant to granzyme B- and perforin-mediated killing than MYD88 wild-type (WT) lymphomas. Interestingly, in the absence of autologous lymphomas, the granzyme B and perforin expression levels in CD8⁺ T cells from patients with MYD88 WT lymphomas and from patients with MYD88 L265P mutant lymphomas were comparable; however, in the presence of autologous lymphomas, the CD8⁺ T cells from patients with MYD88 L265P mutant lymphomas presented significantly lower granzyme B and perforin expression than CD8⁺ T cells from patients with MYD88 WT lymphomas. We further found that the IL-10 expression level and the STAT3 activation level were significantly higher in MYD88 L265P mutant lymphomas than in MYD88 WT lymphomas. Suppressing IL-10 significantly reduced STAT3 activation in both MYD88 WT and MYD88 L265P mutant lymphomas. Blocking either STAT3 or IL-10 could significantly increase the susceptibility of MYD88 L265P mutant lymphomas toward CD8⁺ T cell-mediated cytotoxicity. Together, these data revealed a mechanism of immune evasion in MYD88 L265P mutant lymphomas.

Keywords: DLBCL; IL-10; MYD88; STAT3.