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

in Nature materials by Shivem B Shah, Christopher R Carlson, Kristine Lai, Zhe Zhong, Grazia Marsico, Katherine M Lee, Nicole E Félix Vélez, Elisabeth B Abeles, Mayar Allam, Thomas Hu, Lauren D Walter, Karen E Martin, Khanjan Gandhi, Scott D Butler, Rishi Puri, Angela L McCleary-Wheeler, Wayne Tam, Olivier Elemento, Katsuyoshi Takata, Christian Steidl, David W Scott, Lorena Fontan, Hideki Ueno, Benjamin D Cosgrove, Giorgio Inghirami, Andrés J García, Ahmet F Coskun, Jean L Koff, Ari Melnick, Ankur Singh

TLDR

  • The study investigates how the immune and extracellular matrix cues in the lymphoid tumor microenvironment (Ly-TME) affect the treatment response of activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs). The study identifies rational combinatorial therapies that could improve the treatment response in ABC-DLBCLs, which have significant implications for the field of research and clinical practice.

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.

Overview

  • The study investigates the immune and extracellular matrix cues in the lymphoid tumor microenvironment (Ly-TME) of activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) and builds representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. The study aims to determine how Ly-TME cellular and biophysical factors affect the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signaling pathways in ABC-DLBCL cells, which reduces the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). The primary objective of the study is to identify rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the effects of Ly-TME cellular and biophysical factors on the BCR-MYD88-TLR9 multiprotein supercomplex and cooperative signaling pathways in ABC-DLBCL cells. The results show that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signaling pathways in ABC-DLBCL cells, which reduces the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). The study identifies rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they provide insights into the complex crosstalk between malignant ABC-DLBCL cells and the Ly-TME. The study suggests that combinatorial therapies targeting multiple aberrant signaling pathways could improve the efficacy of treatment in ABC-DLBCL. Future research directions could explore the use of these combinatorial therapies in clinical trials and investigate the potential for personalized medicine approaches based on individual patient Ly-TME profiles.
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