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

• Published in: Nature materials Vol. 22; no. 4; pp. 511 - 523
• Main Authors: Shah, Shivem B., Carlson, Christopher R., Lai, Kristine, Zhong, Zhe, Marsico, Grazia, Lee, Katherine M., Félix Vélez, Nicole E., Abeles, Elisabeth B., Allam, Mayar, Hu, Thomas, Walter, Lauren D., Martin, Karen E., Gandhi, Khanjan, Butler, Scott D., Puri, Rishi, McCleary-Wheeler, Angela L., Tam, Wayne, Elemento, Olivier, Takata, Katsuyoshi, Steidl, Christian, Scott, David W., Fontan, Lorena, Ueno, Hideki, Cosgrove, Benjamin D., Inghirami, Giorgio, García, Andrés J., Coskun, Ahmet F., Koff, Jean L., Melnick, Ari, Singh, Ankur
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2023; Nature Publishing Group
• Subjects: 631/67/70; 639/166/985; Anticancer properties; Attenuation; Biomaterials; Cell Line, Tumor; Chemistry and Materials Science; Combinatorial analysis; Condensed Matter Physics; Effectiveness; Humans; Hydrogels; In vivo methods and tests; Inhibitors; Kinases; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Materials Science; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism; Nanotechnology; NF-kappa B - metabolism; Optical and Electronic Materials; Signal Transduction; Signaling; Translocation; Tumor Microenvironment; Tyrosine
• ISSN: 1476-1122; 1476-4660
• DOI: 10.1038/s41563-023-01495-3

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.
A hydrogel-based modular lymphoma organoid identifies how lymphoid microenvironment cues dampen the effect of MALT1 inhibitors and informs effective combination therapies to rescue the treatment response