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

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.

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Publication Details

Journal
Blood
Published
2025-02-03
DOI
https://doi.org/10.1182/blood.2024025755
Citations
11
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
8.77

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

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

Blanca S. Berrozpe, José A. Martínez-Climent, Marcos Garcia-Lacarte, Óscar Blanco, Sergio Roa, Enrique Goñi, Sara C. Grijalba, Francisco J. Novo, Adrián Arnaiz-Leché, Pablo Umaña, Miguel Canales, Maria Amann, Marién Pascual, Christian Klein, Pablo Sarobe, Javier Melchor, Marı́a A. Burrell, Juan José Lasarte, Iñigo Clemente‐Larramendi, Sandra Morales-Sánchez
article en
11 citations

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.

BloodVol. 145(23)
Roche (Switzerland) (CH), Instituto de Salud Carlos III (ES), Complejo Hospitalario de Salamanca (ES), Navarre Institute of Health Research (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Clinica Universidad de Navarra (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Universidad de Navarra (ES)
Gilead Sciences, F. Hoffmann-La Roche, Technische Universität Dresden, Universidad de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Gobierno de Navarra, Genentech, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 2%
Immune Cell Function and Interaction
8.77
DOIOpen Access PDFOpenAlex
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