Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma

Blood. 2016 Dec 15;128(24):2808-2818. doi: 10.1182/blood-2016-06-720490. Epub 2016 Oct 3.

Abstract

Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antigens, CD20 / immunology
  • CD40 Ligand / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lymphoid Tissue / pathology
  • Lymphoma, Mantle-Cell / pathology*
  • Lymphoma, Mantle-Cell / therapy*
  • Male
  • Mesoderm / pathology
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Targeted Therapy*
  • NF-kappa B / metabolism
  • Tumor Microenvironment* / drug effects
  • Up-Regulation / drug effects
  • bcl-X Protein / metabolism

Substances

  • Antibodies, Monoclonal, Humanized
  • Antigens, CD20
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • bcl-X Protein
  • CD40 Ligand
  • obinutuzumab