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Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment

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Special Issue Information
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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 24508

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Special Issue Editors

Dr. Brian A. Boone

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Guest Editor

Department of Surgery, Department of Microbiology, Immunology and Cell Biology, West Virginia University
Interests: pancreatic cancer, pancreatic tumor microenvironment, pancreatitis, neutrophil extracellular traps, autophagy, damage associated molecular pattern molecules (DAMPs), robotic pancreatic surgery

Dr. Tim D. Eubank

E-Mail Website
Guest Editor

Department of Microbiology, Immunology and Cell Biology, West Virginia University
Interests: tumor macrophage populations and functions, tie2-expressing macrophages, hypoxia, HIF subunits, tumor angiogenesis, VEGF, soluble VEGFR-1, chronic inflammation

Special Issue Information

Dear Colleagues,

Pancreatic cancer results in a unique tumor microenvironment driven by complex interactions between cancer cells, infiltrating immune cells and the surrounding desmoplastic stroma. A chronic inflammatory response results in immunosuppression, limiting the effectiveness of immunotherapies that have shown promise in many other malignancies. This Special Issue will focus on the inflammatory and immune response to pancreatic cancer and its associated treatments. The topics will include but are not limited to:

Mechanisms of immunosuppression
Challenges to effective immunotherapy
Novel immunotherapy strategies in PDAC
Stromal and immune cell crosstalk/signaling
Pancreatic tumor microbiome and associated inflammatory/immune response
Role of inflammation in pancreatic carcinogenesis
Impact of surgical trauma and postsurgical complications on immunosurveillance
Immunomodulation of chemotherapy and radiation treatment
Inflammatory/immune markers of disease prognosis
Regulation of immune cell recruitment factors
Dysregulated tumor angiogenesis leading to hypoxia

Dr. Brian A. Boone
Dr. Tim D. Eubank
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Pancreatic adenocarcinoma
pancreatic tumor microenvironment
tumor associated neutrophils
tumor associated macrophages
inflammation
neutrophil extracellular traps (NETs)
immunotherapy
checkpoint inhibition
CD40
PD-1
PD-L1
CTLA-4
immunosuppression
myeloid derived suppressor cells (MDSCs)
T regulatory cells (Tregs)
microbiome
hypoxia
angiogenesis

Published Papers (7 papers)

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Research

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19 pages, 4255 KiB

Open AccessArticle

Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma

by Ioana Plesca, Iva Benešová, Carolin Beer, Ulrich Sommer, Luise Müller, Rebekka Wehner, Max Heiduk, Daniela Aust, Gustavo Baretton, Michael P Bachmann, Anja Feldmann, Jürgen Weitz, Lena Seifert, Adrian M Seifert and Marc Schmitz

Cancers 2022, 14(5), 1216; https://doi.org/10.3390/cancers14051216 - 26 Feb 2022

Cited by 12 | Viewed by 2853

Abstract

Dendritic cells (DCs) play a key role in the orchestration of antitumor immunity. Activated DCs efficiently enhance antitumor effects mediated by natural killer cells and T lymphocytes. Conversely, tolerogenic DCs essentially contribute to an immunosuppressive tumor microenvironment. Thus, DCs can profoundly influence tumor progression and clinical outcome of tumor patients. To gain novel insights into the role of human DCs in pancreatic ductal adenocarcinoma (PDAC), we explored the frequency, spatial organization, and clinical significance of conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in primary PDAC tissues. A higher density of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s was significantly associated with better disease-free survival (DFS). In addition, an increased frequency of intraepithelial tumor-infiltrating cDC2s was linked to better DFS and overall survival (OS). Furthermore, an increased density of WTA- and TS-infiltrating pDCs tended to improve DFS. Moreover, a higher frequency of WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better DFS and OS. These findings indicate that tumor-infiltrating DCs can significantly influence the clinical outcome of PDAC patients and may contribute to the design of novel treatment options that target PDAC-infiltrating DCs. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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12 pages, 960 KiB

Open AccessArticle

Gemcitabine Plus Nab-Paclitaxel Induces PD-L1 mRNA Expression in Plasma-Derived Microvesicles in Pancreatic Cancer

by Marzia Del Re, Caterina Vivaldi, Eleonora Rofi, Francesca Salani, Stefania Crucitta, Silvia Catanese, Lorenzo Fontanelli, Valentina Massa, Federico Cucchiara, Lorenzo Fornaro, Annalisa Capuano, Stefano Fogli, Enrico Vasile and Romano Danesi

Cancers 2021, 13(15), 3738; https://doi.org/10.3390/cancers13153738 - 25 Jul 2021

Cited by 7 | Viewed by 2701

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005; p = 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004; p = 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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12 pages, 2532 KiB

Open AccessArticle

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

by Lena Seifert, Ioana Plesca, Luise Müller, Ulrich Sommer, Max Heiduk, Janusz von Renesse, David Digomann, Jessica Glück, Anna Klimova, Jürgen Weitz, Marc Schmitz and Adrian M. Seifert

Cancers 2021, 13(6), 1297; https://doi.org/10.3390/cancers13061297 - 15 Mar 2021

Cited by 36 | Viewed by 3584

Abstract

T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8⁺ and Th1-polarized CD4⁺ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3⁺ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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13 pages, 3749 KiB

Open AccessArticle

PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer

by Adrian M. Seifert, Annabel Eymer, Max Heiduk, Rebekka Wehner, Antje Tunger, Janusz von Renesse, Rahel Decker, Daniela E. Aust, Thilo Welsch, Christoph Reissfelder, Jürgen Weitz, Marc Schmitz and Lena Seifert

Cancers 2020, 12(10), 2756; https://doi.org/10.3390/cancers12102756 - 24 Sep 2020

Cited by 15 | Viewed by 3683

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4⁺ T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4⁺ and CD8⁺ T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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Review

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14 pages, 668 KiB

Open AccessReview

Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes

by Alessandro Di Federico, Mirta Mosca, Rachele Pagani, Riccardo Carloni, Giorgio Frega, Andrea De Giglio, Alessandro Rizzo, Dalia Ricci, Simona Tavolari, Mariacristina Di Marco, Andrea Palloni and Giovanni Brandi

Cancers 2022, 14(10), 2429; https://doi.org/10.3390/cancers14102429 - 14 May 2022

Cited by 24 | Viewed by 3471

Abstract

The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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18 pages, 6362 KiB

Open AccessReview

Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer

by Anna Maxi Wandmacher, Anne Letsch and Susanne Sebens

Cancers 2021, 13(16), 4235; https://doi.org/10.3390/cancers13164235 - 23 Aug 2021

Cited by 17 | Viewed by 3562

Abstract

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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24 pages, 1064 KiB

Open AccessReview

The Multifaceted Role of TGF-β in Gastrointestinal Tumors

by Fabio Sabbadini, Monica Bertolini, Serena De Matteis, Domenico Mangiameli, Serena Contarelli, Silvia Pietrobono and Davide Melisi

Cancers 2021, 13(16), 3960; https://doi.org/10.3390/cancers13163960 - 05 Aug 2021

Cited by 18 | Viewed by 3520

Abstract

Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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