Abstract B17: A dual in vivo and in silico system to model ectopic lymph node structure formation and antitumor immune response in the murine tumor microenvironment

2018 ◽  
Author(s):  
Adam W. Mailloux ◽  
Falahat Rana ◽  
Yohsuke Yagawa ◽  
Mark Robertson-Tessi ◽  
Zhou L. Susan ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Tumor Microenvironment ◽  
Structure Formation ◽  
In Silico ◽  
Antitumor Immune Response ◽  
Murine Tumor

scholarly journals IMMU-09. MODULATING THE MYELOID POPULATION IN DIPG MODELS WITH ONCOLYTIC VIRUS AND COMPLEMENT INHIBITORS SHOWS THERAPEUTIC EFFICACY

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i28-i29
Author(s):  
Montserrat Puigdelloses ◽  
Virginia Laspidea ◽  
Dolores Hambardzumyan ◽  
Zhihong Chen ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Oncolytic Virus ◽  
Continuous Production ◽  
Therapeutic Benefit ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Immune Memory ◽  
Inflammatory Microenvironment

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide therapeutic benefit. The complement system promotes tumor progression due to the continuous production of anaphylatoxins leading to the infiltration of myeloid cells, which express high levels of complement receptors (C3aR and C5aR1). We have in silico data showing the high expression of C5aR1 in DIPGs. Thus, we wanted to assess first whether complement C5aR1 could constitute an actionable target, and second whether combining C5aR1 inhibitors with oncolytic virus could result in a superior antitumor immune response than either agent alone in DIPG. In this study, we used two different peptide inhibitors of C5aR1, PMX53 and PMX205 combined with the virus Delta-24-ACT (an oncolytic virus armed with 4-1BBL). We performed in vivo studies to evaluate the efficacy of this combination in immunocompetent DIPG models. Our data showed that the combination Delta-24-ACT/PMX53 significantly extended the median survival of the animals when compared with either agent alone, and led to long-term survivors that generated immune memory. The combination treatment modulated the tumor microenvironment promoting an increase in lymphocytes, mainly CD8+ cells presenting an active phenotype, and a reduction in C5aR1 expression in the myeloid compartment. We are currently evaluating in vivo whether PMX205, which has an improved ability to cross the blood brain barrier, leads to better therapeutic response. In summary, the combination of Delta-24-ACT with a C5aR1 inhibitor showed the capacity to shake the DIPG tumor microenvironment and unleashed an antitumor immune response. These data underscore the possibilities to combine oncolytic virus with targets of the tumor microenvironment to improve their therapeutic benefit in DIPGs.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

scholarly journals HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

2014 ◽  
Vol 34 (4) ◽  
pp. 846-856 ◽  
Author(s):  
Francesca Caccuri ◽  
Christine Rueckert ◽  
Cinzia Giagulli ◽  
Kai Schulze ◽  
Daniele Basta ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Node ◽  
Structure Formation ◽  
Highly Active Antiretroviral Therapy ◽  
Matrix Protein ◽  
Lymphatic Endothelial Cells ◽  
Endothelin 1 ◽  
Tumor Dissemination ◽  
Hiv 1

Objective— AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. Approach and Results— Human primary lymph node–derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node–derived lymphatic endothelial cells and activating the Akt/extracellular signal–regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node–derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. Conclusions— Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

In vivo resistance of secondary antitumor immune response to cyclophosphamide: effects on T cell subsets

1987 ◽  
Vol 24 (1) ◽  
Author(s):  
Samuele Peppoloni ◽  
BonnieJ. Mathieson ◽  
RonaldB. Herberman ◽  
RoyW. Overton ◽  
Eliezer Gorelik
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Antitumor Immune Response ◽  
T Cell Subsets

scholarly journals Robust Phagocyte Recruitment Controls the Opportunistic Fungal PathogenMucor circinelloidesin Innate GranulomasIn Vivo

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Sarah Inglesfield ◽  
Aleksandra Jasiulewicz ◽  
Matthew Hopwood ◽  
James Tyrrell ◽  
George Youlden ◽  
...  
Keyword(s):  
Immune Response ◽  
Fungal Infection ◽  
Real Time ◽  
Clinical Management ◽  
In Silico ◽  
Innate Immune ◽  
Granuloma Formation ◽  
Early Immune Response ◽  
Latent Stage

ABSTRACTMucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection byMucor circinelloidesspores are modeled by a combinedin silicomodeling approach and real-timein vivomicroscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onsetin vivo.In silicoanalysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. Thesein silicodata are supported by anin vivolack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomasin vivo. Disease can be reactivated by immunosuppression. Together, these data represent the firstin vivoreal-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients.IMPORTANCEMucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.

scholarly journals CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

2019 ◽  
Author(s):  
Weiling He ◽  
Hui Zhang ◽  
Shuhua Li ◽  
Yongmei Cui ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Sodium Dodecyl ◽  
Antitumor Immune Response ◽  
Patient Derived Xenograft ◽  
Poliovirus Receptor

AbstractLung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.AbbreviationsLUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

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