Three-dimensional models: a novel approach for lymphoma research

Rossi, Mosè; Alviano, Francesco; Righi, Simona; Sabattini, Elena; Agostinelli, Claudio

doi:10.1007/s00432-021-03897-9

Cited by 10 publications

(4 citation statements)

References 87 publications

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“…Unlike the cellular monocultures from which spheroids are derived, the variety of stem cells producing organoids can selfrenew and differentiate into multiple lineages in vitro; this renewal process is responsible for an organoid's greater longevity. While patient-derived tumor organoids and patient-derived spheroids (tumorspheres) have a place in cancer research and precision medicine strategies, the more functionally advanced organoid can be sourced as a living tissue biobank, provide disease-specific models, and (like some spheroids) be useful in drug screening (15)(16)(17). The spheroid and organoids are now being developed and getting used for several FMi research (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Three-dimensional Organ Systemsmentioning

confidence: 99%

Review on new approach methods to gain insight into the feto-maternal interface physiology

Menon,

Muglia,

Levin

2023

Front. Med.

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Non-human animals represent a large and important feature in the history of biomedical research. The validity of their use, in terms of reproducible outcomes and translational confidence to the human situation, as well as ethical concerns surrounding that use, have been and remain controversial topics. Over the last 10 years, the communities developing microphysiological systems (MPS) have produced new approach method (NAMs) such as organoids and organs-on-a-chip. These alternative methodologies have shown indications of greater reliability and translatability than animal use in some areas, represent more humane substitutions for animals in these settings, and – with continued scientific effort – may change the conduct of basic research, clinical studies, safety testing, and drug development. Here, we present an introduction to these more human-relevant methodologies and suggest how a suite of pregnancy associated feto-maternal interface system-oriented NAMs may be integrated as reliable partial-/full animal replacements for investigators, significantly aid animal-/environmental welfare, and improve healthcare outcomes.

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Section: Three-dimensional Organ Systemsmentioning

confidence: 99%

Review on new approach methods to gain insight into the feto-maternal interface physiology

Menon,

Muglia,

Levin

2023

Front. Med.

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“…In the last years there has been an evolution toward patient-derived 3D cultures and organoids (PDO) in many cancer types [ 26 ]. However, those systems are scarce in lymphoma [ 27 , 28 ] and not previously generated in MCL. In the era of personalized medicine and with the rapid evolution of immunotherapies, there is an urgent need to establish these systems that recapitulate disease activated pathway and immune profile, and are able to induce T-cell mediated responses.…”

Section: Introductionmentioning

confidence: 99%

A novel patient-derived 3D model recapitulates mantle cell lymphoma lymph node signaling, immune profile and in vivo ibrutinib responses

et al. 2023

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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 toward personalized therapeutic approaches.

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“…[12][13][14][15] In contrast to solid cancers, relevant 3D models for B-NHL are poorly described. 16 Among them, spheroids/organoids from DLBCL cell lines or fresh samples from patients are the most developed. [17][18][19][20][21] We are pioneers in the development of 3D cultures established from FL cell lines demonstrating that conventional 2D culture of lymphoma B cells does not reproduce FL signaling pathways [22][23][24][25][26] while a 3D hanging-drop (HD) system that we term HD-MALC (multicellular aggregates of lymphoma cells) recapitulates FL transcriptomic profiles including the overexpression of gene families involved in survival pathways (ie, NF-κB pathway, cell cycle regulation, hypoxia).…”

Section: Introductionmentioning

confidence: 99%

Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine

Faria,

Gava,

Gravelle

et al. 2023

J Immunother Cancer

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BackgroundFollicular lymphoma (FL), the most common indolent non-Hodgkin’s Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses.MethodsTo capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability.ResultsFL-PDLS, mainly composed of tumor B cells (60% on average) and autologous T cells (13% CD4 and 3% CD8 on average, respectively), rapidly organizes into patient-specific three-dimensional (3D) structures of three different morphotypes according to 3D imaging analysis. RNAseq analysis indicates that FL-PDLS reproduces FL hallmarks with the overexpression of cell cycle, BCR, or mTOR signaling related gene sets. FL-PDLS also recapitulates the exhausted immune phenotype typical of FL-LN, including expression of BTLA, TIGIT, PD-1, TIM-3, CD39 and CD73 on CD3+T cells. These features render FL-PDLS an amenable system for immunotherapy testing. With this aim, we demonstrate that the combination of obinutuzumab (anti-CD20) and nivolumab (anti-PD1) reduces tumor load in a significant proportion of FL-PDLS. Interestingly, B cell depletion inversely correlates with the percentage of CD8+cells positive for PD-1 and TIM-3.ConclusionsIn summary, FL-PDLS is a robust patient-derived 3D system that can be used as a tool to mimic FL pathology and to test novel immunotherapeutic approaches in a context of personalized medicine.

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Three-dimensional models: a novel approach for lymphoma research

Cited by 10 publications

References 87 publications

Review on new approach methods to gain insight into the feto-maternal interface physiology

Review on new approach methods to gain insight into the feto-maternal interface physiology

A novel patient-derived 3D model recapitulates mantle cell lymphoma lymph node signaling, immune profile and in vivo ibrutinib responses

Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine

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