Treatment of arthritis by macrophage depletion and immunomodulation: Testing an apoptosis-mediated therapy in a humanized death receptor mouse model

BackgroundTumour-associated macrophages (TAM) play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages have been identified not only in invasive tumours, but also in early preinvasive pancreatic intraepithelial neoplasias and are known to mediate tumour progression.MethodsWe aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in the genetic mouse model of pancreatic cancer (KPC mouse: LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre). KPC mice were treated with liposomal clodronate or control liposomes from week 8 to week 20. Tumour and metastasis formation as well as alterations in local and circulating immune cells and cytokines were analysed.ResultsTreatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. Tumour incidence and size was only slightly reduced. However, metastasis formation in the liver und lungs was markedly diminished after macrophage depletion. Reduced macrophage count was associated with significant alterations in circulating growth factors and mediators known to be secreted by macrophages and associated with angiogenesis, most prominently VEGF. Moreover, application of liposomal clodronate led to marked alterations in circulating immune cells, among them reduced regulatory T cells.ConclusionsPharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with modulated profile of both secreted mediators and regulatory T cells. Pharmacological modulation of infiltrating macrophages represents a promising avenue for antimetastatic therapeutic approaches.

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Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes

Diabetologia ◽

10.1007/s00125-014-3407-5 ◽

2014 ◽

Vol 58 (1) ◽

pp. 140-148 ◽

Cited By ~ 12

Author(s):

Yuxing Zhao ◽

Nicholas A. Scott ◽

Stacey Fynch ◽

Lorraine Elkerbout ◽

W. Wei-Lynn Wong ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Mouse Model ◽

Death Receptor ◽

Autoreactive T Cells

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Abstract B85: Combination therapy using the programmed death receptor-1 and the programmed death-ligand 1 inhibitors and Fluorouracil in human colorectal carcinoma in a humanized patient-derived orthotopic mouse model

10.1158/2326-6074.tumimm19-b85 ◽

2020 ◽

Author(s):

Xin Zhang ◽

Grace Maresh ◽

Linh Hellmers ◽

Henry Yip ◽

Lara McKean Baste ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Combination Therapy ◽

Mouse Model ◽

Death Receptor ◽

Orthotopic Mouse Model ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Human Colorectal Carcinoma

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Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

International Journal of Molecular Sciences ◽

10.3390/ijms22084176 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4176

Author(s):

Maria Buñuales ◽

Maria Cristina Ballesteros-Briones ◽

Manuela Gonzalez-Aparicio ◽

Sandra Hervas-Stubbs ◽

Eva Martisova ◽

...

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Peritoneal Carcinomatosis ◽

Checkpoint Inhibitors ◽

High Capacity ◽

Systemic Exposure ◽

Blocking Antibody ◽

Macrophage Depletion ◽

Polycytidylic Acid ◽

Gene Therapy Vectors

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.

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A protocol for macrophage depletion and reconstitution in a mouse model of sepsis

STAR Protocols ◽

10.1016/j.xpro.2021.101004 ◽

2021 ◽

Vol 2 (4) ◽

pp. 101004

Author(s):

Tivoli Nguyen ◽

Jie Du ◽

Yan Chun Li

Keyword(s):

Mouse Model ◽

Macrophage Depletion

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Macrophages inhibit and enhance endometriosis depending on their origin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013776118 ◽

2021 ◽

Vol 118 (6) ◽

pp. e2013776118 ◽

Cited By ~ 1

Author(s):

Chloe Hogg ◽

Kavita Panir ◽

Priya Dhami ◽

Matthew Rosser ◽

Matthias Mack ◽

...

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Peritoneal Macrophage ◽

Peritoneal Macrophages ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

Macrophage Depletion ◽

Monocyte Recruitment ◽

Macrophage Populations ◽

And Function

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are “proendometriosis” while newly recruited monocyte-derived macrophages, possibly in LpM form, are “antiendometriosis.” These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.

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Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer’s disease

Cell Death and Disease ◽

10.1038/s41419-021-04165-x ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Chiara Burgaletto ◽

Chiara Bianca Maria Platania ◽

Giulia Di Benedetto ◽

Antonio Munafò ◽

Giovanni Giurdanella ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Mirna Gene ◽

Death Receptor ◽

Amyloid Β ◽

Age Related Macular Degeneration ◽

Protein Accumulation ◽

Model Of Alzheimer’S Disease ◽

Age Related

AbstractAge-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.

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