ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression.

in Cell death and differentiation by Martina Antoniolli, Maria Solovey, Johannes Adrian Hildebrand, Tabea Freyholdt, Carolin Dorothea Strobl, Deepak Bararia, William David Keay, Louisa Adolph, Michael Heide, Verena Passerini, Lis Winter, Lucas Wange, Wolfgang Enard, Susanne Thieme, Helmut Blum, Martina Rudelius, Julia Mergner, Christina Ludwig, Sebastian Bultmann, Marc Schmidt-Supprian, Heinrich Leonhardt, Marion Subklewe, Michael von Bergwelt-Baildon, Maria Colomé-Tatché, Oliver Weigert

TLDR

  • The study found that ARID1A mutations can lead to decreased FAS protein expression in FL, making lymphoma cells resistant to FASLG-induced apoptosis and impacting CAR T cell killing.
  • The findings suggest a novel mechanism by which FL cells can escape FAS-dependent immune surveillance.

Abstract

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility ("openness"). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced-stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis, and significantly diminished CAR T cell killing in functional experiments. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including CAR T cells.

Overview

  • The study focuses on the regulation of the FAS receptor and its ligand (FASLG) in the context of follicular lymphoma (FL) and the role of ARID1A mutations in this process.
  • The researchers analyzed 151 FL biopsies and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%.
  • The study aimed to investigate the mechanism by which ARID1A mutations contribute to FL pathogenesis, with a focus on the regulation of FAS and FASLG.

Comparative Analysis & Findings

  • The study found that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population compared to wild-type FL.
  • Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression.
  • The study identified a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression.

Implications and Future Directions

  • The findings suggest that ARID1A mutations can contribute to FL pathogenesis by disrupting the regulation of FAS and FASLG.
  • Understanding the mechanisms by which ARID1A mutations affect FAS regulation may have implications for the development of targeted therapies for FL.
  • Future studies should investigate the prevalence and clinical significance of ARID1A mutations in FL and explore the potential of targeting FAS in FL therapy.
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