IL-10 from tumoral B cells modulates the diffuse large B-cell lymphoma microenvironment and response to immunotherapy
Abstract
Abstract The contribution of interleukin-10 (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–like (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knockout 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 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, which is refractory to PD-1 immune checkpoint blockade. 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 the survival of malignant B cells, whereas the paracrine action of B-cell–derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies targeting the lymphoma microenvironment. Furthermore, IL-10–associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Thus, our work provides important functional and mechanistic insights into the role of B-cell–derived IL-10 in the biology of ABC-DLBCL.
Article Details
Authors (20)
Marcos Garcia-Lacarte
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Sara C. Grijalba
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Javier Melchor
3Navarra Institute for Health Research, Pamplona, Spain
Marién Pascual
3Navarra Institute for Health Research, Pamplona, Spain
Enrique Goñi
Iñigo Clemente-Larramendi
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Sandra Morales-Sánchez
6Department of Pathology, Anatomy and Physiology, Universidad de Navarra, Pamplona, Spain
María A. Burrell
3Navarra Institute for Health Research, Pamplona, Spain
Oscar Blanco
7Department of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain
Adrián Arnaiz-Leché
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Blanca S. Berrozpe
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Maria Amann
8Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
Christian Klein
Pablo Umaña
1Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland
Miguel Canales
5Clínica Universidad de Navarra, Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), Pamplona, Spain
José Ángel Martinez-Climent
2Hemato-Oncology Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Juan J. Lasarte
2Cancer Center Clínica Universidad de Navarra, Pamplona, Spain
Pablo Sarobe
2Cancer Center Clínica Universidad de Navarra, Pamplona, Spain
Francisco J. Novo
1Department of Biochemistry and Genetics, Universidad de Navarra, Pamplona, Spain
Sergio Roa
2Centre for Applied Medical Research (CIMA), Hematology and Oncology Program, Pamplona, Spain