scholarly journals CCL2 produced by pancreatic ductal adenocarcinoma is essential for the accumulation and activation of monocytic myeloid‐derived suppressor cells

2021 ◽  
Author(s):  
Haitao Gu ◽  
Wensheng Deng ◽  
Zhong Zheng ◽  
Ke Wu ◽  
Feng Sun
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells

scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

scholarly journals Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma

2019 ◽  
Vol 216 (3) ◽  
pp. 656-673 ◽  
Author(s):  
Jing Liu ◽  
Wenna Jiang ◽  
Kaili Zhao ◽  
Hongwei Wang ◽  
Tianxing Zhou ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cd8 T Cells ◽  
Response Rate ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Immune Microenvironment ◽  
Gm Csf ◽  
Ets Homologous Factor ◽  
Efficacy Prediction

Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

scholarly journals Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1627 ◽  
Author(s):  
Anita Thyagarajan ◽  
Mamdouh Salman A. Alshehri ◽  
Kelly L.R. Miller ◽  
Catherine M. Sherwin ◽  
Jeffrey B. Travers ◽  
...  
Keyword(s):  
Survival Rates ◽  
Suppressor Cells ◽  
Cell Types ◽  
Therapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Resistance ◽  
Cellular Mechanisms ◽  
Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

scholarly journals Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in Mutant Kras Mice

2020 ◽  
Author(s):  
Yi Liu ◽  
Yasunori Deguchi ◽  
Daoyan Wei ◽  
Micheline J. Moussalli ◽  
Donghui Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
High Fat Diet ◽  
Suppressor Cells ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
High Fat ◽  
Pancreatic Cancers ◽  
Genetic Deletion ◽  
Targeted Inhibition

AbstractPro-obesity high-fat diet is linked with an increased incidence of pancreatic cancers, but the molecular underpinnings of this association remain poorly understood. Here, we report that PPARD is upregulated in pancreatic intraepithelial neoplasia lesions (PanINs) at early stages of pancreatic tumorigenesis in humans and mutant Kras mice. Transgenic overexpression of Ppard in pancreatic epithelial cells drastically accelerates the development and progression of pancreatic ductal adenocarcinoma in mutant Kras mice when activated by feeding the mice with a high-fat diet or a diet containing GW501516 (50 mg/kg), a selective PPARD agonist. In contrast, pancreatic Ppard genetic deletion significantly suppressed the promotion of pancreatic tumorigenesis by these diets. Mechanistically, we found that this Ppard hyperactivation in pancreatic epithelial cells of mutant Kras mice increased production of chemokines and cytokines (e.g., CcI2, CcI4-5, CxcI5 and II6), leading to the robustly increased recruitment of myeloid-derived suppressor cells and macrophages into pancreata, which fostered an immune suppressive microenvironment and subsequently accelerated pancreatic ductal adenocarcinoma development and progression. Our findings demonstrate that PPARD plays an essential role in the promotion of pancreatic tumorigenesis by a high-fat diet. Targeted inhibition of PPARD activation is a potential interventive strategy for pancreatic cancer prevention and therapy.

scholarly journals P03.11 Exploring tumor-intrinsic factors regulating the recruitment of myeloid-derived suppressor cells (MDSC) in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A26.2-A27
Author(s):  
C Rambuscheck ◽  
P Metzger ◽  
C Hörth ◽  
R Hennel ◽  
S Bärthel ◽  
...  
Keyword(s):  
Cell Lines ◽  
Immune Cell ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Immune Cell Infiltration ◽  
Myeloid Derived Suppressor Cells ◽  
Pdac Cell ◽  
Immunosuppressive Tumor Microenvironment

BackgroundPancreatic Ductal Adenocarcinoma (PDAC) has very poor 5-year overall survival rate. Despite the encouraging effect of immunotherapy in other cancer types, clinical benefit in PDAC patients remains limited. One of the reasons for the lack of success is the immunosuppressive tumor microenvironment (TME), which is maintained by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. High MDSC infiltration is associated with a poor survival in PDAC patients. Our project aims at identifying tumor-driven chemokines that influence recruitment of MDSC and establishment of the immunosuppressive tumor microenvironment.Materials and Methods45 PDAC cell lines generated from spontaneous tumors of genetically-modified mice harboring the characteristic driver mutations KrasG12D or PIK3CAH1047R were analyzed for their expression levels of CXCL1, CCL2, G-CSF and GM-CSF by qRT-PCR. In order to study the relationship between the chemokine/cytokine profile and the immune cell infiltration, selected tumor cell lines were implanted orthotopically in C57BL6 mice. Three weeks after inoculation blood, spleen and tumor were isolated and organ specific immune cell infiltration was analyzed by flow cytometry. To further characterize tumor-secreted factors tumor conditioned medium was generated and the concentration of 33 chemokines was analyzed in a multiplex assay. The chemokine levels were correlated with migratory capacity of splenic MDSC measured in an ex vivo chemotaxis assay.ResultsCXCL1 significantly enhanced migration of polymorphonuclear MDSC (PMN-MDSC) in vitro, while migration of monocytic MDSC (M-MDSC) was predominantly skewed towards CCL2. Three weeks after tumor inoculation, MDSC populations in blood and spleen were expanded. Most intriguingly, PDAC cell lines with high CXCL1 or CCL2 levels in vitro showed significantly enriched intratumoral accumulation of PMN-MDSC and M-MDSC, respectively, suggesting that tumor-intrinsic chemokine secretion and not factors from the tumor stroma determined MDSC infiltration. The ex vivo chemotaxis assays revealed additional factors that modulate migration of MDSC into the TME.ConclusionsThe in vitro gene expression levels of individual chemokines (CXCL1 and CCL2) determines the MDSC infiltration in vivo into the TME. Targeting the chemokine-receptor axis of MDSC subpopulations could be a promising approach in the treatment of pancreatic cancer.FundingThe project was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projektnummer 329628492 - SFB 1321 and the Förderprogramm für Forschung und Lehre (FöFoLe) funded by the Ludwig-Maximilians-Universität München.Disclosure InformationC. Rambuscheck: None. P. Metzger: None. C. Hörth: None. R. Hennel: None. S. Bärthel: None. C. Falcomatà: None. K. Lauber: None. S. Endres: None. D. Saur: None. M. Schnurr: None. L.M. König: None.

471 Pancreatic cancer therapy based on combination of DNA vaccination and PI3Kgamma inhibition

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A501-A501
Author(s):  
Francesco Novelli ◽  
Claudia Curcio ◽  
Cecilia Roux ◽  
Laura Conti ◽  
Roberta Curto ◽  
...  
Keyword(s):  
Tumor Size ◽  
Combined Therapy ◽  
Critical Role ◽  
Suppressor Cells ◽  
Dna Vaccination ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Ministry Of Health ◽  
Proteomic Approach ◽  
Kpc Mice

BackgroundPancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer mortality in developed countries, with one of the poorest prognoses among all cancers. Although 10–15% of patients are candidates for gross total surgical resection, recurrence is frequent, and the overall 5-year survival rate is around 8%. Using a proteomic approach, we have identified alpha-Enolase 1 (ENO1) as PDA-associated antigens. We have shown that ENO1 DNA vaccination efficiently prolongs survival of engineered mice that spontaneously develop PDA (both KC and KPC mice). Recently, we have demonstrated that PI3K gamma play a critical role in PDA by driving the recruitment of myeloid derived suppressor cells into tumor tissues and it’s genetic or pharmacologic inhibition effectively inhibits PDA progression and metastasis. In this study we assessed the hypothesis that targeting myeloid derived suppressor cells, via pharmacological PI3Kgamma inhibition, synergizes with ENO1 DNA vaccination by inducing a strong and sustained immune response.MethodsKPC mice were vaccinated 4 times with ENO1 starting at 4 weeks of age; 2 weeks after the last immunization mice were treated with the PI3Kgamma inhibitor TG100-115 (2,5 mg/kg), for further two weeks. At sacrifice neoplastic lesions, immune infiltrate, T and B cell response were analyzed.ResultsMice that received ENO1 and TG100-115 therapy showed a significant decrease in tumor size compared to both ENO1 and PBS treated mice. Moreover, the analysis of pancreas tissues indicated that combined therapy induced an increased number of CD8 and F4/80 cells and a decrease of FoxP3, CD31 and NG2 cells compared to control mice. In addition, we extract mRNA from formalin fixed paraffin embedded pancreas tissues of treated mice. We observed an increase of Granzyme B in both ENO1 and ENO1+TG100-115 and a down modulation of genes involved in fibroblast and stellate cell activation suggesting a modulation of microenvironment in the combined therapy group.ConclusionsTreatment with ENO1 plus TG100-115 is able to reduce tumor size in pancreas, increase immune cell infiltration and modulate stroma cell compartment, making the therapy a suitable approach for PDA treatment.AcknowledgementsThis work was supported by grants from the Italian Ministry of Health-Progetti Ricerca Finalizzata (RF-2013-02354892 to FN), Associazione Italiana Ricerca sul Cancro (5 × mille no. 12182 to FN, IG no. 15257 to FN); University of Turin-Progetti Ateneo 2014-Compagnia di San Paolo (PC-METAIMMUN- OTHER to FN and PANTHER to PC), Fondazione Ricerca Molinette Onlus, Fondazione Nadia Valsecchi.Ethics ApprovalAll animal experiments were approved by the University of Torino, Italian Ministry of Health and performed in accordance with EU laws in the animal facility of the Molecular Biotechnology Center (MBC). Reference no: 378/2015-PR and 597/2019-PR.

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