A novel Patient-Derived 3D Model Recapitulates Mantle Cell Lymphoma Lymph Node Signaling, Immune Profile and in vivo Ibrutinib Responses

Abstract

Mantle cell lymphoma (MCL), a rare and aggressive B cell non-Hodgkin lymphoma, mainly develops in the lymph node (LN) and creates a protective and immunosuppressive niche that facilitates tumor survival, proliferation and chemoresistance. To capture disease heterogeneity and tumor microenvironment (TME) cues, we have developed the first patient-derived MCL spheroids (MCL-PDLS) that recapitulate tumor oncogenic pathways and immune microenvironment in a multiplexed system that allows easy drug screening, including immunotherapies. MCL spheroids, integrated by tumor B cells, monocytes and autologous T cells self-organize in disc-shaped structures, where B and T cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. RNA-seq analysis demonstrated that tumor cells recapitulate hallmarks of MCL-LN (proliferation, NF-kB and BCR), with T cells exhibiting an exhaustion profile (PD1, TIM-3 and TIGIT). MCL-PDLS reproduces in vivo responses to ibrutinib and demonstrates that combination of ibrutinib with nivolumab (anti-PD1) may be effective in ibrutinib-resistant cases by engaging an immune response with increased interferon gamma and granzyme B release. In conclusion, MCL-PDLS recapitulates specific MCL-LN features and in vivo responses to ibrutinib, representing a robust tool to study MCL interaction with the immune TME and to perform drug screening in a patient-derived system, advancing towards personalized therapeutic approaches.

Emerging Strategies in 3D Culture Models for Hematological Cancers

“…Recently, Araujo‐Ayala et al generated a 3D spheroid model of LN TME of mantle cell lymphoma (MCL), which recapitulates in vivo responses to target therapies. They demonstrate that this model fairly represents fundamental hallmarks of MCL microenvironment features as proliferation signature, BCR signaling pathway, and immune TME exhaustion 36 …”

“…They demonstrate that this model fairly represents fundamental hallmarks of MCL microenvironment features as proliferation signature, BCR signaling pathway, and immune TME exhaustion. 36…”

“…(2023) 7:8 www.hemaspherejournal.com 36 A limitation of spheroid models is poor diffusion of oxygen and nutrients in the inner core of the structure, which depends on the size of the sample. In addition, spheroids are difficult to handle outside the seeding platform and tend to self-disassemble, especially when using nonadherent cells as lymphocytes.…”