IL-10 from tumoral B cells modulates the diffuse large B-cell lymphoma microenvironment and response to immunotherapy

• IL-10 secretion by DLBCL cells prevents the drift of the lymphoma microenvironment toward a highly immune-suppressive state

• Hallmarks of lymphoma IL-10 deficiency predict R-CHOP response but reflect poor antitumor immunity in preclinical models and DLBCL patients

The contribution of IL-10 secreted by tumoral B cells to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knock-out of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated, but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T cell (Treg) depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, refractory to PD-1 immune checkpoint blockade (ICB). However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes survival of malignant B cells, while the paracrine action of B cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies aimed at the lymphoma microenvironment (LME). Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of DLBCL patients treated with R-CHOP. Thus, our work provides important functional and mechanistic insights into the role of B cell-derived IL-10 in the biology of ABC-DLBCL.