Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma

Stirm, Kristin; Leary, Peter; Bertram, Katrin; Núñez, Nicolás Gonzalo; Wüst, Daria; Boudesco, Christophe; Verhoeyen, Els; Zenz, Thorsten; Menter, Thomas; Tzankov, Alexandar; Müller, Anne

doi:10.1080/2162402x.2021.2003533

Cited by 27 publications

(23 citation statements)

References 38 publications

(44 reference statements)

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“…22 The presence of Foxp3 + Tregs not further subclassified by additional markers is mostly considered to be beneficial 23 25 ; in contrast, the infiltration of 'effector' regulatory T-cells, coexpressing inhibitory markers such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or T-cell immunoglobulin and mucin domain 3 (TIM-3) along with Foxp3, is usually associated with a poor prognosis, 24 26 as is a high Treg count in the blood of patients with DLBCL. 27 We have previously shown that DLBCL arising on a background of immunosuppression due to solid organ transplantation are generally devoid of Treg infiltration 28 and also lack many of the above-mentioned genetic adaptations of immune escape, such as immuneevasive B2M mutations. 7 We demonstrate here that Tregs form an integral part of the lymphoma microenvironment not only in human DLBCL but also in a MYC-driven serial transplantation model of the disease, where up to 80% of intratumoral CD4 + T-cells are Foxp3 + Tregs.…”

Section: How This Study Might Affect Research Practice or Policymentioning

confidence: 99%

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

Stirm

Leary

Wüst

et al. 2023

J Immunother Cancer

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BackgroundRoughly half of all diffuse large B-cell lymphomas (DLBCLs) are infiltrated by large numbers of regulatory T-cells (Tregs). Although the presence of ‘effector’ Tregs in particular is associated with an inferior prognosis in patients on standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy, the role of this cell type during lymphoma initiation and progression is poorly understood.MethodsHere, we use tissue microarrays containing prospectively collected DLBCL patient specimens, as well as data from publicly available cohorts to explore the mutational landscape of Treg-infiltrated DLBCL. We further take advantage of a model of MYC-driven lymphoma to mechanistically dissect the contribution of Tregs to lymphoma pathogenesis and to develop a strategy of Treg-selective interleukin-2 (IL-2) starvation to improve immune control of MYC-driven lymphoma.ResultsWe find that all genetic DLBCL subtypes, except for one characterized by co-occurringMYD88/CD79mutations, are heavily infiltrated by Tregs. Spectral flow cytometry and scRNA-sequencing reveal the robust expression of functional and immunosuppressive markers on Tregs infiltrating MYC-driven lymphomas; notably, we find that intratumoral Tregs arise due to local conversion from naïve CD4+precursors on tumor contact. Treg ablation in Foxp3iDTRmice, or by antibody-mediated Treg-selective blockade of IL-2 signaling, strongly reduces the lymphoma burden. We identify lymphoma B-cells as a major source of IL-2, and show that the effects of Treg depletion are reversed by the simultaneous depletion of Foxp3-negative CD4+T-cells, but not CD8+T-cells or natural killer (NK) cells. The inhibition of ATP hydrolyzation and adenosine production by Tregs at least partly phenocopies the effects of Treg depletion. Treg depletion further synergizes with pro-apoptotic CD40 activation to sustain durable responses.ConclusionThe combined data implicate Tregs as a potential therapeutic target in DLBCL, especially in combination with other immunotherapies.

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Section: How This Study Might Affect Research Practice or Policymentioning

confidence: 99%

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

Stirm

Leary

Wüst

et al. 2023

J Immunother Cancer

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“…A recent study ( 15 ) focused on IL-10, as it is well known to activate signal transducer and activator of transcription (STAT) 3 in vitro in DLBCL cases. Furthermore, high serum levels of IL-10 are strongly correlated with a poor survival ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Refractory Primary Vitreoretinal Lymphoma Involving the Spinal Cord with a Temporary Complete Response to Tirabrutinib

et al. 2023

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Many patients with primary vitreoretinal lymphoma (PVRL) exhibit central nervous system (CNS) involvement either at the diagnosis or during follow-up. The prognosis in the patients of PVRL with relapsed or refractory CNS remains extremely poor. We herein report a patient with refractory PVRL who had recurrence in the spinal cord despite receiving high-dose methotrexate-based chemotherapy and whole-brain radiotherapy. The patient surprisingly responded to tirabrutinib temporarily. We believe that this case suggests the utility of this new target therapy.

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“…Moreover, a specific subset of regulatory B cells termed B10 cells that produced IL-10 was recently found to inhibit immunotherapy-mediated clearance of non-Hodgkin’s B lymphoma cells ( 53 ). In addition to inhibiting immunotherapy, the secretion of IL-10 by PEL has also been shown to confer immune escape ( 54 ) and drug resistance ( 55 ). One potential explanation is that IL-10 works in autocrine/paracrine loops to induce the antiapoptotic effect in non-Hodgkin’s B-cell lymphoma ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

SUMO Modification of Histone Demethylase KDM4A in Kaposi’s Sarcoma-Associated Herpesvirus-Induced Primary Effusion Lymphoma

Yeh

Chen

Yang

et al. 2022

J Virol

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Tumor cell-derived IL-10 promotes cell-autonomous growth and immune escape in diffuse large B-cell lymphoma

Cited by 27 publications

References 38 publications

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

Treg-selective IL-2 starvation synergizes with CD40 activation to sustain durable responses in lymphoma models

Refractory Primary Vitreoretinal Lymphoma Involving the Spinal Cord with a Temporary Complete Response to Tirabrutinib

SUMO Modification of Histone Demethylase KDM4A in Kaposi’s Sarcoma-Associated Herpesvirus-Induced Primary Effusion Lymphoma

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