scholarly journals Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

2022 ◽  
Author(s):  
Erika Y. Faraoni ◽  
Nirav C. Thosani ◽  
Baylee O'Brien ◽  
Lincoln N. Strickland ◽  
Victoria Y. Mota ◽  
...  
Keyword(s):  
Radiofrequency Ablation ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
New Combination ◽  
Ductal Adenocarcinoma ◽  
Tumor Growth Rate ◽  
Therapeutic Success ◽  
Syngeneic Mouse Model

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. Methods: To test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. Results: RFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. Conclusions: These data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Keywords: tumor associated macrophages; IL-23; tumor vasculature; ablation induced necrosis

scholarly journals Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mengwen Zhang ◽  
Xingyi Pan ◽  
Kenji Fujiwara ◽  
Noelle Jurcak ◽  
Stephen Muth ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mouse Model ◽  
Tumor Cells ◽  
Ductal Adenocarcinoma ◽  
Cell Contact ◽  
Tumor Associated Macrophages ◽  
Glucose Response ◽  
Pancreatic Cancer Cells ◽  
Syngeneic Mouse Model ◽  
Direct Cell

AbstractHow tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

scholarly journals Characterization of Circulating IL-7R Positive Cell Populations for Early Detection of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 10 (18) ◽  
pp. 4157
Author(s):  
Sun-Hee Heo ◽  
Sung Ill Jang ◽  
So Young Kim ◽  
Bongkun Choi ◽  
Dong Ki Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Patients ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Effector Memory ◽  
Discrete Subset ◽  
Normal Individuals ◽  
Syngeneic Mouse Model

(1) Background: Pancreatic cancer is a high devastating disease with the lowest survival rate among all common cancers due to difficulties in early diagnosis. The purpose of this study was to identify and characterize the distinct subset of blood cell population elevated in peripheral blood mononuclear cells (PBMC) of pancreatic cancer to evaluate the potential markers for diagnosis of pancreatic cancer; (2) Methods: We analyzed differential gene expression in PBMC from normal individuals and pancreatic cancer patients utilizing transcriptome analysis. Flow cytometry analysis was applied to identify the discrete subset of interleukin-7 receptor (IL-7R) expressing cells in these cells. The expression of IL-7R during tumorigenesis was determined in syngeneic mouse model of pancreatic cancer in vivo; (3) Results: PBMC from pancreatic cancer patients expressed elevated IL-7R mRNA compared to healthy control individuals. IL-7R expressing cells rapidly appeared from the early stages of the onset of tumor formation in syngeneic pancreatic cancer mouse model in vivo. The discrete subset of IL-7R positive cells mainly consist of naive T, central memory T, and effector memory T cells; (4) Conclusions: Taken together, our present findings suggest that pancreatic cancer patients expressed higher level of IL-7R expression in PBMC that rapidly emerged from the onset of early pancreatic tumor formation in vivo than normal individuals. Thus, it can be used as a novel biological marker for early events of pancreatic cancer development.

Abstract P264: Targeting oxygen metabolism reduces hypoxia in the tumor microenvironment of a syngeneic mouse model

2021 ◽  
Author(s):  
Daan F. Boreel ◽  
Paul Span ◽  
Hans Peters ◽  
Renske J.E. van den Bijgaart ◽  
Sandra Heskamp ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Oxygen Metabolism ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

scholarly journals Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hong-Bo Li ◽  
Zi-Han Yang ◽  
Qing-Qu Guo
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Immune Effector ◽  
Effector Cells ◽  
Pathological Subtype

AbstractPancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

scholarly journals Abstract 1872: Fluorescence-guided surgery in the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma

2017 ◽  
Author(s):  
Kosuke Hasegawa ◽  
Atsushi Suetsugu ◽  
Miki Nakamura ◽  
Takuro Matsumoto ◽  
Takahiro Kunisada ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Guided Surgery ◽  
Syngeneic Mouse ◽  
Fluorescence Guided Surgery ◽  
Syngeneic Mouse Model

scholarly journals Pancreatic Cancer and Immunotherapy: A Clinical Overview

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4138
Author(s):  
Florentine E. F. Timmer ◽  
Bart Geboers ◽  
Sanne Nieuwenhuizen ◽  
Madelon Dijkstra ◽  
Evelien A. C. Schouten ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Successful Implementation ◽  
Cell Therapies ◽  
Radio Therapy ◽  
Wide Range

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

Abstract 4110: Color-coded imaging of the tumor microenvironment of malignant lymphoma in a syngeneic mouse model

2016 ◽  
Author(s):  
Takuro Matsumoto ◽  
Atsushi Suetsugu ◽  
Kosuke Hasegawa ◽  
Miki Nakamura ◽  
Hitomi Aoki ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mouse Model ◽  
Malignant Lymphoma ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

The role of macrophage production of transforming growth factor-ß in epithelial ovarian cancer progression.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17100-e17100
Author(s):  
Brandon Roane ◽  
Michael J. Birrer ◽  
Whitney Goldsberry ◽  
Rebecca Christian Arend
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Growth Factor ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Transforming Growth Factor ◽  
Tumor Challenge ◽  
Syngeneic Mouse Model ◽  
Significant Difference ◽  
Omental Tumor

e17100 Background: Increased Transforming Growth Factor- ß (TGF-ß) signaling is associated with poorer prognosis in advanced stage epithelial ovarian carcinoma (EOC). Macrophages are known to produce high amounts of TGF-ß which plays a significant role in immune suppression in the tumor microenvironment Methods: A syngeneic mouse model was created using ID8 cell lines with p53 knocked out. These cells were injected intraperitoneally to establish tumor challenge. One mouse model was treated with TGF-ß monoclonal antibody at the time of tumor inoculation. A second model utilized a mouse line that was engineered to eliminate production of TGF-ß from macrophages specifically. Tumors were harvested and weighed after 42 days of tumor challenge. Flow cytometry was used to analyze differences in CD8 T-cell and T regulatory cell populations. Results: Tumor weights were significantly reduced in mice treated with anti-TGF-ß monoclonal antibody (p = 0.02). Average tumor weights were 125mg vs 101mg comparing non-treated to treated mice. Also, ascites volume was measured using syringe aspiration from peritoneal cavity at the time of sacrifice. Mean ascites volume was 4.7mL vs 2.9 mL (p = 0.004) in untreated mice versus mice treated with monoclonal antibody. In mice with macrophages specific deletion of TGF-ß production, tumors were unable to be established in these mice and omental weights were comparable to tumor naive mice with a mean weight of 34mg compared to 115 mg in wild type mice. In both mouse models there was a significant difference in CD8 : Tregs ratio in omental tumor microenvironment. Conclusions: Increased amounts of TGF-ß contribute to increased tumor invasion and migration, while loss of TGF-ß results in both a decrease in tumor burden and a decrease in suppressors of T cell activity. Inhibition of TGF-ß, demonstrated with a monoclonal antibody can effectively reduce TGF-β signaling. The macrophages within the omental tumor microenvironment are a source of large amounts of TGF-ß and when lost result in an inability to establish tumors in intraperitoneal tumors.

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