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

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-x 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.

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

“…7,9 Coculture of MCL cells with L-CD40L fibroblasts resulted in more resistance to ROR1 2A2 treatment (but not for Granta-519 with low ROR1 levels; Figure 3H), suggesting that microenvironment-mediated survival signals can modulate ROR1-targeted therapies and these findings are clinically relevant.…”

“…L-CD40L fibroblast coculturing of cell lines and primary cells was done as previously described. 9 MCL cell lines Jeko-1, Mino, Maver-1, Z-138, Hbl-2, Granta-519, Rec-1, SP53, CLL-like MEC-1, MEC-2, and epithelial adenocarcinoma Hela cells were used in this study. Cells were grown in RPMI 1640 media (Lonza, Basel, Switzerland), Iscove modified Dulbecco medium (Life Technologies, Carlsbad, CA) for Z-138, Granta-519, MEC-1 and MEC-2, or Dulbecco modified Eagle medium (Lonza) for Hela cells, supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and penicillin/streptomycin and incubated at 37°C and 5% CO 2 .…”

“…7 Therefore, therapeutic targeting of the Bcl-2 family of proteins is a promising strategy, especially for overcoming MCL drug resistance. [7][8][9] Receptor tyrosine kinase-like orphan receptors 1 and 2 (ROR1 and ROR2) are the only members of the ROR family from the noncanonical Wnt family of receptors. 10,11 RORs are type I transmembrane receptors considered as pseudokinases due to alterations in their canonical tyrosine kinase motifs.…”

Development of venetoclax for therapy of lymphoid malignancies

“…58 CD40-induced proliferation and mitochondrial priming loss in MCL can also be overcome by the second-generation anti-CD20 antibody obinutuzumab, 60 which blocks induction of BCL-xL by inhibiting the activation of the NF-κB signaling pathway. A series of clinical trials have begun to investigate the efficacy of venetoclax plus anti-CD20 monoclonal antibodies and chemoimmunotherapy in patients with CLL and lymphoma (Table 2).…”

“…58,59 Similarly, by mimicking the microenvironment through CD40 stimulation, ABT-199 sensitivity was compromised through activation of the NF-κB pathway and upregulation of BCL-xL in MCL. 48,60 Moreover, the extracellular acid sensing G-protein coupled receptor, GPR65, is expressed in primary CLL cells, where its levels correlate strongly with those of antiapoptotic BCL-2 family members. …”