Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy arising from germinal center or post-germinal center B-cells that retain many of the properties of normal B-cells. Here we show that a subset of DLBCL express the cytokine IL-10 and its receptor. The genetic ablation of IL-10 receptor...
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Taylor & Francis Group
2021
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oai:doaj.org-article:1d829b2258f141b2b3b452c988a055342021-11-26T11:19:49ZTumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma2162-402X10.1080/2162402X.2021.2003533https://doaj.org/article/1d829b2258f141b2b3b452c988a055342021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.2003533https://doaj.org/toc/2162-402XDiffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy arising from germinal center or post-germinal center B-cells that retain many of the properties of normal B-cells. Here we show that a subset of DLBCL express the cytokine IL-10 and its receptor. The genetic ablation of IL-10 receptor signaling abrogates the autocrine STAT3 phosphorylation triggered by tumor cell-intrinsic IL-10 expression and impairs growth of DLBCL cell lines in subcutaneous and orthotopic xenotransplantation models. Furthermore, we demonstrate using an immunocompetent Myc-driven model of DLBCL that neutralization of IL-10 signaling reduces tumor growth, which can be attributed to reduced Treg infiltration, stronger intratumoral effector T-cell responses, and restored tumor-specific MHCII expression. The effects of IL-10R neutralization were phenocopied by the genetic ablation of IL-10 signaling in the Treg compartment and could be reversed by MHCII blockade. The BTK inhibitor ibrutinib effectively blocked tumor cell-intrinsic IL-10 expression and tumor growth in this Myc-driven model. Tumors from patients with high IL-10RA expression are infiltrated by higher numbers of Tregs than IL-10RAlow patients. Finally, we show in 16 cases of DLBCL derived from transplant patients on immunosuppressive therapy that IL-10RA expression is less common in this cohort, and Treg infiltration is not observed.Kristin StirmPeter LearyKatrin BertramNicolás Gonzalo NúñezDaria WüstChristophe BoudescoEls VerhoeyenThorsten ZenzBurkhard BecherThomas MenterAlexandar TzankovAnne MüllerTaylor & Francis Grouparticlelymphoma microenvironmentdlbcl mouse modelsoncogenic stat3 signalingpersonalized treatmentcancer immunotherapyImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
lymphoma microenvironment dlbcl mouse models oncogenic stat3 signaling personalized treatment cancer immunotherapy Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
lymphoma microenvironment dlbcl mouse models oncogenic stat3 signaling personalized treatment cancer immunotherapy Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kristin Stirm Peter Leary Katrin Bertram Nicolás Gonzalo Núñez Daria Wüst Christophe Boudesco Els Verhoeyen Thorsten Zenz Burkhard Becher Thomas Menter Alexandar Tzankov Anne Müller Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| description |
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy arising from germinal center or post-germinal center B-cells that retain many of the properties of normal B-cells. Here we show that a subset of DLBCL express the cytokine IL-10 and its receptor. The genetic ablation of IL-10 receptor signaling abrogates the autocrine STAT3 phosphorylation triggered by tumor cell-intrinsic IL-10 expression and impairs growth of DLBCL cell lines in subcutaneous and orthotopic xenotransplantation models. Furthermore, we demonstrate using an immunocompetent Myc-driven model of DLBCL that neutralization of IL-10 signaling reduces tumor growth, which can be attributed to reduced Treg infiltration, stronger intratumoral effector T-cell responses, and restored tumor-specific MHCII expression. The effects of IL-10R neutralization were phenocopied by the genetic ablation of IL-10 signaling in the Treg compartment and could be reversed by MHCII blockade. The BTK inhibitor ibrutinib effectively blocked tumor cell-intrinsic IL-10 expression and tumor growth in this Myc-driven model. Tumors from patients with high IL-10RA expression are infiltrated by higher numbers of Tregs than IL-10RAlow patients. Finally, we show in 16 cases of DLBCL derived from transplant patients on immunosuppressive therapy that IL-10RA expression is less common in this cohort, and Treg infiltration is not observed. |
| format |
article |
| author |
Kristin Stirm Peter Leary Katrin Bertram Nicolás Gonzalo Núñez Daria Wüst Christophe Boudesco Els Verhoeyen Thorsten Zenz Burkhard Becher Thomas Menter Alexandar Tzankov Anne Müller |
| author_facet |
Kristin Stirm Peter Leary Katrin Bertram Nicolás Gonzalo Núñez Daria Wüst Christophe Boudesco Els Verhoeyen Thorsten Zenz Burkhard Becher Thomas Menter Alexandar Tzankov Anne Müller |
| author_sort |
Kristin Stirm |
| title |
Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| title_short |
Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| title_full |
Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| title_fullStr |
Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| title_full_unstemmed |
Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma |
| title_sort |
tumor cell-derived il-10 promotes cell-autonomous growth and immune escape in diffuse large b-cell lymphoma |
| publisher |
Taylor & Francis Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/1d829b2258f141b2b3b452c988a05534 |
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