Radiation Therapy in Combination with Hyperthermia and Immunotherapy Inhibit Pancreatic Tumor Growth and Modulate Tumor Microenvironment in Mice

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70–80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.

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Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth

ACS Nano ◽

10.1021/acsnano.6b02231 ◽

2016 ◽

Vol 10 (12) ◽

pp. 10636-10651 ◽

Cited By ~ 66

Author(s):

Sounik Saha ◽

Xunhao Xiong ◽

Prabir K. Chakraborty ◽

Khader Shameer ◽

Rochelle R. Arvizo ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Gold Nanoparticle ◽

Pancreatic Tumor

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Integrin β1 Promotes Pancreatic Tumor Growth by Upregulating Kindlin-2 and TGF-β Receptor-2

International Journal of Molecular Sciences ◽

10.3390/ijms221910599 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10599

Author(s):

Md Saimon Mia ◽

Yagna Jarajapu ◽

Reena Rao ◽

Sijo Mathew

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Pancreatic Tumor ◽

Critical Role ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Integrin Β1 ◽

Surface Receptors ◽

3D Matrix ◽

Β Receptor

The tumor microenvironment plays a critical role in defining the growth and malignancy of solid tumors. Extracellular matrix (ECM) proteins such as collagen, vitronectin, and fibronectin are major components of the tumor microenvironment. Tumor growth-promoting reciprocal interaction between ECM and cytoplasmic proteins is regulated by the cell surface receptors called integrins. This study investigated the mechanism by which integrin β1 promotes pancreatic tumor growth. In MIA PaCa-2 pancreatic cancer cell line, the loss of integrin β1 protein reduced the ability of cells to proliferate in a 3D matrix and compromised the ability to form a focal adhesion complex. Decreased expression of integrin α5 was observed in KO cells, which resulted in impaired cell spreading and adhesion on vitronectin and fibronectin. Reduced expression of the integrin-associated protein, kindlin-2 was also recorded. The downregulation of kindlin-2 decreased the phosphorylation of Smad2/3 by reducing the expression of TGF-β receptor 2. These results unravel a new mechanism of integrin β1 in tumor growth by modifying the expression of kindlin-2 and TGF-β receptor 2 signaling.

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Abstract B32: GRP55 antagonists alter tumor microenvironment and inhibit tumor growth in a pancreatic tumor xenograft model

10.1158/1538-7445.panca16-b32 ◽

2016 ◽

Author(s):

Nagendra S. Singh ◽

Irving W. Wainer

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Pancreatic Tumor ◽

Xenograft Model ◽

Tumor Xenograft ◽

Inhibit Tumor Growth

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Role of Protein kinase D2 in pancreatic tumor growth and tumor angiogenesis

Zeitschrift für Gastroenterologie ◽

10.1055/s-0030-1263395 ◽

2010 ◽

Vol 48 (08) ◽

Author(s):

N Azoitei ◽

GV Pusapati ◽

A Kleger ◽

C Brunner ◽

F Genze ◽

...

Keyword(s):

Protein Kinase ◽

Tumor Growth ◽

Tumor Angiogenesis ◽

Pancreatic Tumor

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The Inhibition Effect of Caveolin-1 on PANC1 Human Pancreatic Tumor Growth In vitro and In vivo*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2011.00168 ◽

2012 ◽

Vol 38 (12) ◽

pp. 1121-1131

Author(s):

Xiao-Hui WANG ◽

Ya-Min ZHENG ◽

Ye-Qing CUI ◽

Shuang LIU ◽

Hai-Chen SUN ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Tumor ◽

Caveolin 1 ◽

Inhibition Effect

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695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0695 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A737-A737

Author(s):

Loise Francisco-Anderson ◽

Mary Abdou ◽

Michael Goldberg ◽

Erin Troy ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Extracellular Vesicles ◽

Tumor Immunity ◽

Extracellular Vesicle ◽

The Body ◽

Checkpoint Inhibition ◽

Small Intestinal ◽

The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

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A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

Scientific Reports ◽

10.1038/s41598-021-94837-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. Farias ◽

A. Soto ◽

F. Puttur ◽

C. J. Goldin ◽

S. Sosa ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Therapeutic Effect ◽

Immune Cells ◽

Immune Checkpoint ◽

Combined Treatment ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Regulatory Cells ◽

Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

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Intratumoral Canine Distemper Virus Infection Inhibits Tumor Growth by Modulation of the Tumor Microenvironment in a Murine Xenograft Model of Canine Histiocytic Sarcoma

International Journal of Molecular Sciences ◽

10.3390/ijms22073578 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3578

Author(s):

Federico Armando ◽

Adnan Fayyad ◽

Stefanie Arms ◽

Yvonne Barthel ◽

Dirk Schaudien ◽

...

Keyword(s):

Tumor Microenvironment ◽

Virus Infection ◽

Tumor Growth ◽

Canine Distemper Virus ◽

Xenograft Model ◽

Histiocytic Sarcoma ◽

Oncolytic Viruses ◽

Canine Distemper ◽

Murine Xenograft Model ◽

The Impact

Histiocytic sarcomas refer to highly aggressive tumors with a poor prognosis that respond poorly to conventional treatment approaches. Oncolytic viruses, which have gained significant traction as a cancer therapy in recent decades, represent a promising option for treating histiocytic sarcomas through their replication and/or by modulating the tumor microenvironment. The live attenuated canine distemper virus (CDV) vaccine strain Onderstepoort represents an attractive candidate for oncolytic viral therapy. In the present study, oncolytic virotherapy with CDV was used to investigate the impact of this virus infection on tumor cell growth through direct oncolytic effects or by virus-mediated modulation of the tumor microenvironment with special emphasis on angiogenesis, expression of selected MMPs and TIMP-1 and tumor-associated macrophages in a murine xenograft model of canine histiocytic sarcoma. Treatment of mice with xenotransplanted canine histiocytic sarcomas using CDV induced overt retardation in tumor progression accompanied by necrosis of neoplastic cells, increased numbers of intratumoral macrophages, reduced angiogenesis and modulation of the expression of MMPs and TIMP-1. The present data suggest that CDV inhibits tumor growth in a multifactorial way, including direct cell lysis and reduction of angiogenesis and modulation of MMPs and their inhibitor TIMP-1, providing further support for the concept of its role in oncolytic therapies.

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