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  3. Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas

  • Nat Mater. 2023 Apr;22(4):511-523. doi: 10.1038/s41563-023-01495-3.
Shivem B Shah 1 2,  Christopher R Carlson 3 4,  Kristine Lai 3 4,  Zhe Zhong 3 4,  Grazia Marsico 3 4,  Katherine M Lee 1,  Nicole E Félix Vélez 5,  Elisabeth B Abeles 6,  Mayar Allam 3,  Thomas Hu 3,  Lauren D Walter 7,  Karen E Martin 4,  Khanjan Gandhi 8,  Scott D Butler 9,  Rishi Puri 9,  Angela L McCleary-Wheeler 9,  Wayne Tam 10,  Olivier Elemento 11,  Katsuyoshi Takata 12 13,  Christian Steidl 12 14,  David W Scott 12 14,  Lorena Fontan 15 16,  Hideki Ueno 17,  Benjamin D Cosgrove 1,  Giorgio Inghirami 10,  Andrés J García 4 18,  Ahmet F Coskun 3,  Jean L Koff 8,  Ari Melnick 15,  Ankur Singh 19 20 21 22
Affiliations

Affiliations

  • 1 Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
  • 2 Columbia University, New York, USA.
  • 3 Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
  • 4 Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
  • 5 College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA.
  • 6 College of Arts and Sciences, Cornell University, Ithaca, NY, USA.
  • 7 Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, USA.
  • 8 Winship Cancer Center, Emory University School of Medicine, Atlanta, GA, USA.
  • 9 College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
  • 10 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 11 Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 12 Centre for Lymphoid Cancer, British Columbia Cancer Center, Vancouver, British Columbia, Canada.
  • 13 Niigata University, Niigata, Japan.
  • 14 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 15 Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 16 Janssen Pharmaceuticals, Inc., Beerse, Belgium.
  • 17 Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 18 Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
  • 19 Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA. ankur.singh@gatech.edu.
  • 20 Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA. ankur.singh@gatech.edu.
  • 21 Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. ankur.singh@gatech.edu.
  • 22 Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA. ankur.singh@gatech.edu.
PMID: 36928381 DOI: 10.1038/s41563-023-01495-3
Abstract

Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like Receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

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