Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma

Saleh, Khalil; Cheminant, Morgane; Chiron, David; Burroni, Barbara; Ribrag, Vincent; Sarkozy, Clémentine

doi:10.3390/cancers14133229

Cited by 15 publications

(12 citation statements)

References 112 publications

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“…First, both tumor B cells and autologous T cells maintain good viability and engage proliferation for at least 1-week, a window which allows to analyze the efficacy of most therapeutic agents. It is fundamental to consider the myeloid compartment as a part of the MCL niche, disease pathogenesis and a source of immunosuppressive signals [ 20 , 21 , 45 ]. As the percentage of autologous monocytes in the original PB sample was extremely low due to tumor B-cell expansion [ 46 ], we decided to introduce monocytes from healthy donors in a ratio that reflects macrophage infiltration in MCL biopsies [ 31 ].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…We next investigated SI-10 in an A20 immunocompetent syngeneic mouse model of B cell lymphoma. With increasing knowledge of the tumor microenvironment, preclinical studies show that the TME plays a signi cant role in drug resistance to current therapies [24]. The A20 model exhibits clinical characteristics of MCL in vivo, including in ltration of the bone marrow and liver, and enlargement of the spleen [25].…”

Section: Si-10 Inhibition Extends Survival In a Syngeneic Tumor Modelmentioning

confidence: 99%

Inhibition of SRC-3 as a potential therapeutic strategy for aggressive mantle cell lymphoma

Bijou

Liu

et al. 2023

Preprint

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Mantle cell lymphoma (MCL) is a heterogeneous disease with a poor prognosis. Despite years of research in MCL, relapse occurs in patients with current therapeutic options necessitating the development of novel therapeutic agents. Previous attempts to pharmacologically inhibit SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas, and previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin’s lymphoma patients. This suggests that SRC-3 may play a role in the progression of B cell lymphoma and that the development of selective SRC inhibitors should be investigated. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in a panel of MCL cell lines in vitro by resazurin assay. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. SI-10 treatment resulted in dose-dependent cytotoxicity in a panel of MCL cell lines in vitro. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.

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“… 1 , 2 Recently, several new therapeutic strategies including noncovalent Bruton tyrosine kinase inhibitors, bispecific antibodies, and next generation chimeric antigen receptor T-cell therapy have been developed and shown promising results in the relapsed/refractory settings. 3 , 4 …”

Section: Introductionmentioning

confidence: 99%

SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma

Abdelrazak Morsy,

Lilienthal,

Lord

et al. 2024

Blood

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The sterile alpha motif and histidine-aspartate (HD) domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several haematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Co-immunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.

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Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma

Cited by 15 publications

References 112 publications

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

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

Inhibition of SRC-3 as a potential therapeutic strategy for aggressive mantle cell lymphoma

SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma

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