Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas PMID: 36928381

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
20. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA. [email protected].
21. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].
22. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA. [email protected].

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.