M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma

Shen, Long; Li, Honghao; Shi, Yuzhi; Wang, Dekun; Gong, Junbo; Xun, Jing; Zhou, Sifan; Xiang, Rong; Tan, Xiaoyue

doi:10.1038/srep30347

Cited by 89 publications

(83 citation statements)

References 32 publications

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“…Additionally, although TAMs have been associated with immunomodulation in other tumor types, their functional role has not yet been fully defined within the lymphoma microenvironment. In DLBCL, TAMs were defined in the TME as CD68 pos or CD68 pos CD163 pos and their prognostic impact remains controversial [15,55,56]. In particular, differing correlations with clinical outcome were observed and appeared to depend on the way TAMs were defined (i.e., as CD68 pos , CD163 pos , or CD68 pos CD163 pos ) and whether treatments included the anti-CD20 antibody Rituximab or not [57].…”

Section: In Germinal Center B-cell Lymphomas Myeloid Regulatory Cellmentioning

confidence: 99%

Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Roussel

Irish

Ménard

et al. 2017

Cancer Immunol Immunother

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In lymphomas arising from the germinal center, prognostic factors are linked to the myeloid compartment. In particular, high circulating monocyte or myeloid-derived suppressor cell counts are associated with poor prognosis for patients with high-grade B-cell lymphomas. Macrophages with an M2 phenotype are enriched within lymphoma tumors. However, the M1/M2 nomenclature is now deprecated and the clinical impact of this phenotype remains controversial. Across cancer types, myeloid cells are primarily thought to function as immune suppressors during tumor initiation and maintenance, but the biological mechanisms behind the myeloid signatures are still poorly understood in germinal center B-cell lymphomas. Herein, we describe the role and clinical relevance of myeloid cells in B-cell lymphoma and propose innovative approaches to decipher this complex cellular compartment. Indeed, characterization of this heterogeneous cell ecosystem has been largely accomplished with "low-resolution" approaches like morphological evaluation and immunohistochemistry, where cells are characterized using a few proteins and qualitative metrics. High-resolution, quantitative approaches, such as mass cytometry, are valuable to better understand myeloid cell diversity, functions, and to identify potential targets for novel therapies.

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Section: In Germinal Center B-cell Lymphomas Myeloid Regulatory Cellmentioning

confidence: 99%

Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Roussel

Irish

Ménard

et al. 2017

Cancer Immunol Immunother

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“…26 The data on pathogenic and prognostic effects of M2 macrophages in nodal DLBCL are controversial. [27][28][29] Nevertheless, Shen et al 30 demonstrated that the number of M2 macrophages correlated negatively with prognosis in nodal DLBCL.…”

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confidence: 99%

Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma—New Therapeutic Targets

Mitteldorf

Berisha²,

Pfaltz³

et al. 2017

American Journal of Surgical Pathology

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Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma.

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“…The different localization patterns of legumain in and around tumor cells suggest site‐specific functions. Shen et al . reported that tumor‐associated M2 macrophages induced extracellular matrix degradation and the stimulation of angiogenesis by overexpressing legumain, thus promoting the progression of diffuse large B‐cell lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Legumain correlates with neuroblastoma differentiation and can be used in prodrug design

et al. 2017

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Neuroblastoma (NB) is a highly malignant solid tumor in children. The cysteine endopeptidase legumain is expressed in adult solid tumors, but its expression in NB has not been examined. In this study, we assayed legumain expression in two NB cell lines and in microarrays of tumor tissues collected from 46 children with undifferentiated NB, differentiated NB, and ganglioneuroblastoma. Correlation analyses showed that legumain was expressed in all NB cell lines tested and that expression correlated with the degree of tumor differentiation. The efficacy, specificity, and toxicity of EMC-AANL-DOX, a novel doxorubicin-based legumain-activated prodrug, were then evaluated in mouse model of NB. Compared with DOX, EMC-AANL-DOX showed greater inhibition of tumor growth and a lower toxicity at high doses. Neither leukocyte or platelet counts nor renal function or cardiac anatomy differed significantly between the EMC-AANL-DOX and control groups (p > .05), suggesting that the prodrug caused minimal bone marrow depression and did not induce renal or cardiac damage. The good specificity and efficacy of EMC-AANL-DOX and low toxicity recommend its use in the treatment of NB. Correlation analyses of NB differentiation and legumain expression may reveal a novel anti-tumor-related functions of the drug and a new strategy for the treatment of pediatric solid tumors.

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M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma

Cited by 89 publications

References 32 publications

Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma—New Therapeutic Targets

Legumain correlates with neuroblastoma differentiation and can be used in prodrug design

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