Distinct Peripheral T-cell and NK-cell Profiles In HGBL-MYC/BCL2 versus DLBCL NOS Patients.

High-grade B-cell lymphoma patients with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immuno-chemotherapy compared to diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) patients without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T-cells and NK-cells of HGBL-MYC/BCL2 patients (n=66), DLBCL NOS patients (n=53) and age-matched healthy donors (HDs, n=16) by flow cytometry and performed proliferation, cytokine production and cytotoxicity assays. As compared to HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T-cells, but decreased CD4+ T-cells. Regulatory T-cell (Treg) frequencies were reduced only in DLBCL NOS patients. Activated (HLA-DR+/CD38+) T-cells, PD-1+CD4+ T-cells and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T-cells were increased only in HGBL-MYC/BCL2. DLBCL NOS patients, but not HGBL-MYC/BCL2 patients, exhibited higher frequencies of senescent T-cells compared to HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T-cells of HGBL-MYC/BCL2 patients were exhausted with impaired cytokine production and degranulation. DLBCL NOS patients, but not HGBL-MYC/BCL2 patients, exhibited higher frequencies of NK-cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+ and DNAM-1+ expressing NK-cells. Although NK-cells of HGBL-MYC/BCL2 patients showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T-cells of HGBL-MYC/BCL2 patients. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance to investigate potential immune evasion in the microenvironment of MYC-rearranged lymphomas.