T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells

Abstract

In diffuse large B-cell lymphoma (DLBCL), the number of circulating monocytes and neutrophils represents an independent prognostic factor. These cell subsets include monocytic and granulocytic myeloid derived suppressor cells (M- and G-MDSCs) defined by their ability to suppress T-cell responses. MDSCs are a heterogeneous population described in inflammatory and infectious diseases as well as in numerous tumors including multiple myeloma, chronic lymphocytic leukemia and DLBCL. However, their mechanisms of action remain unclear. We broadly assessed the presence and mechanisms of suppression of MDSC subsets in DLBCL. First, a myeloid suppressive signature was identified by gene expression profiling in DLBCL peripheral blood. Accordingly, we identified in a cohort of 66 DLBCL patients an increase in circulating G-MDSC (Lin^negHLA-DR^negCD33^posCD11b^pos) and M-MDSC (CD14^posHLA-DR^low) counts. Interestingly, only M-MDSC number was correlated with the International Prognostic Index (IPI), the event-free survival (EFS), and the number of circulating T_reg. Furthermore, T-cell proliferation was restored after monocyte depletion. Myeloid-dependent T-cell suppression was attributed to a release of IL-10 and S100A12 and an increased PD-L1 expression. In summary, we identified expanded MDSC subsets in DLBCL as well as new mechanisms of immunosuppression in DLBCL.