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Pancreatic Neoplasms: HELP
Articles by Maria Pia Protti
Based on 5 articles published since 2010
(Why 5 articles?)
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Between 2010 and 2020, Maria P. Protti wrote the following 5 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer. 2019

Brunetto, Emanuela / De Monte, Lucia / Balzano, Gianpaolo / Camisa, Barbara / Laino, Vincenzo / Riba, Michela / Heltai, Silvia / Bianchi, Marco / Bordignon, Claudio / Falconi, Massimo / Bondanza, Attilio / Doglioni, Claudio / Protti, Maria Pia. ·Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. · Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit and Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Innovative Immunotherapies Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · MolMed SpA, Milan, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. protti.mariapia@hsr.it. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. protti.mariapia@hsr.it. ·J Immunother Cancer · Pubmed #30760333.

ABSTRACT: BACKGROUND: The thymic stromal lymphopoietin (TSLP), a key cytokine for development of Th2 immunity, is produced by cancer associated fibroblasts (CAFs) in pancreatic cancer where predominant tumor infiltrating Th2 over Th1 cells correlates with reduced patients' survival. Which cells and molecules are mostly relevant in driving TSLP secretion by CAFs in pancreatic cancer is not defined. METHODS: We performed in vitro, in vivo and ex-vivo analyses. For in vitro studies we used pancreatic cancer cell lines, primary CAFs cultures, and THP1 cells. TSLP secretion by CAFs was used as a read-out system to identify in vitro relevant tumor-derived inflammatory cytokines and molecules. For in vivo studies human pancreatic cancer cells and CAFs were orthotopically injected in immunodeficient mice. For ex-vivo studies immunohistochemistry was performed to detect ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) expression in surgical samples. Bioinformatics was applied to interrogate published data sets. RESULTS: We show in vitro that IL-1α and IL-1β released by pancreatic cancer cells and tumor cell-conditioned macrophages are crucial for TSLP secretion by CAFs. Treatment of immunodeficient mice orthotopically injected with human IL-1 positive pancreatic cancer cells plus CAFs using the IL-1R antagonist anakinra significantly reduced TSLP expression in the tumor. Importantly, we found that pancreatic cancer cells release alarmins, among which ASC, able to induce IL-1β secretion in macrophages. The relevance of ASC was confirmed ex-vivo by its expression in both tumor cells and tumor associated macrophages in pancreatic cancer surgical samples and survival data analyses showing statistically significant inverse correlation between ASC expression and survival in pancreatic cancer patients. CONCLUSIONS: Our findings indicate that tumor released IL-1α and IL-1β and ASC are key regulators of TSLP secretion by CAFs and their targeting should ultimately dampen Th2 inflammation and improve overall survival in pancreatic cancer.

2 Article Loss of P53 Function Activates JAK2-STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated With Patient Survival. 2016

Wörmann, Sonja M / Song, Liang / Ai, Jiaoyu / Diakopoulos, Kalliope N / Kurkowski, Magdalena U / Görgülü, Kivanc / Ruess, Dietrich / Campbell, Andrew / Doglioni, Claudio / Jodrell, Duncan / Neesse, Albrecht / Demir, Ihsan E / Karpathaki, Angelica-Phaedra / Barenboim, Maxim / Hagemann, Thorsten / Rose-John, Stefan / Sansom, Owen / Schmid, Roland M / Protti, Maria P / Lesina, Marina / Algül, Hana. ·II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Beatson Institute for Cancer Research, University of Glasgow, Glasgow, United Kingdom. · Pathology Unit, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy. · Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom. · Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University, Marburg, Germany. · Chirurgische Klinik und Poliklinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. · Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, United Kingdom. · Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany. · Tumor Immunology Unit, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@mri.tum.de. ·Gastroenterology · Pubmed #27003603.

ABSTRACT: BACKGROUND & AIMS: One treatment strategy for pancreatic ductal adenocarcinoma is to modify, rather than deplete, the tumor stroma. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) is associated with progression of pancreatic and other solid tumors. We investigated whether loss of P53 function contributes to persistent activation of STAT3 and modification of the pancreatic tumor stroma in patients and mice. METHODS: Stat3, Il6st (encodes gp130), or Trp53 were disrupted, or a mutant form of P53 (P53R172H) or transgenic sgp130 were expressed, in mice that developed pancreatic tumors resulting from expression of activated KRAS (KrasG12D, KC mice). Pancreata were collected and analyzed by immunohistochemistry, in situ hybridization, quantitative reverse-transcription polymerase chain reaction (qPCR), or immunoblot assays; fluorescence-activated cell sorting was performed to identify immune cells. We obtained frozen pancreatic tumor specimens from patients and measured levels of phosphorylated STAT3 and P53 by immunohistochemistry; protein levels were associated with survival using Kaplan-Meier analyses. We measured levels of STAT3, P53, ligands for gp130, interleukin 6, cytokines, sonic hedgehog signaling, STAT3 phosphorylation (activation), and accumulation of reactive oxygen species in primary pancreatic cells from mice. Mice with pancreatic tumors were given gemcitabine and a Janus kinase 2 (JAK2) inhibitor; tumor growth was monitored by 3-dimensional ultrasound. RESULTS: STAT3 was phosphorylated constitutively in pancreatic tumor cells from KC mice with loss or mutation of P53. Tumor cells of these mice accumulated reactive oxygen species and had lower activity of the phosphatase SHP2 and prolonged phosphorylation of JAK2 compared with tumors from KC mice with functional P53. These processes did not require the gp130 receptor. Genetic disruption of Stat3 in mice, or pharmacologic inhibitors of JAK2 or STAT3 activation, reduced fibrosis and the numbers of pancreatic stellate cells in the tumor stroma and altered the types of immune cells that infiltrated tumors. Mice given a combination of gemcitabine and a JAK2 inhibitor formed smaller tumors and survived longer than mice given control agents; the tumor stroma had fewer activated pancreatic stellate cells, lower levels of periostin, and alterations in collagen production and organization. Phosphorylation of STAT3 correlated with P53 mutation and features of infiltrating immune cells in human pancreatic tumors. Patients whose tumors had lower levels of phosphorylated STAT3 and functional P53 had significantly longer survival times than patients with high levels of phosphorylated STAT3 and P53 mutation. CONCLUSIONS: In pancreatic tumors of mice, loss of P53 function activates JAK2-STAT3 signaling, which promotes modification of the tumor stroma and tumor growth and resistance to gemcitabine. In human pancreatic tumors, STAT3 phosphorylation correlated with P53 mutation and patient survival time. Inhibitors of this pathway slow tumor growth and stroma formation, alter immune cell infiltration, and prolong survival of mice. Transcript profiling: ArrayExpress accession number: E-MTAB-3278.

3 Article Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients. 2016

De Monte, Lucia / Wörmann, Sonja / Brunetto, Emanuela / Heltai, Silvia / Magliacane, Gilda / Reni, Michele / Paganoni, Anna Maria / Recalde, Helios / Mondino, Anna / Falconi, Massimo / Aleotti, Francesca / Balzano, Gianpaolo / Algül, Hana / Doglioni, Claudio / Protti, Maria Pia. ·Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. San Raffaele Vita-Salute University, Milan, Italy. · Pathology Unit, IRCCS, San Raffaele Hospital, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Medical Oncology Department, IRCCS, San Raffaele Hospital, Milan, Italy. · Laboratory for Modeling and Scientific Computing (MOX), Dipartimento di Matematica, Politecnico di Milano, Milan, Italy. · Hematology, Ospedale San Matteo, Pavia, Italy. · Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Lymphocyte Activation Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · San Raffaele Vita-Salute University, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Pancreatic Surgery Unit, IRCCS, San Raffaele Hospital, Milan, Italy. · Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. Pancreatic Surgery Unit, IRCCS, San Raffaele Hospital, Milan, Italy. · San Raffaele Vita-Salute University, Milan, Italy. Pathology Unit, IRCCS, San Raffaele Hospital, Milan, Italy. Division of Experimental Oncology, IRCCS, San Raffaele Scientific Institute, Milan, Italy. · Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy. Division of Immunology, Transplantation and Infectious Diseases, IRCCS, San Raffaele Scientific Institute, Milan, Italy. m.protti@hsr.it. ·Cancer Res · Pubmed #26873846.

ABSTRACT: In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell-derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer. Cancer Res; 76(7); 1792-803. ©2016 AACR.

4 Article Immune infiltrates as predictive markers of survival in pancreatic cancer patients. 2013

Protti, Maria Pia / De Monte, Lucia. ·Tumor Immunology Unit, Transplantation and Infectious Diseases, San Raffaele Scientific Institute Milan, Italy ; Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute Milan, Italy. ·Front Physiol · Pubmed #23950747.

ABSTRACT: Pancreatic cancer is a devastating disease with dismal prognosis. The tumor microenvironment is composed by multiple cell types, molecular factors, and extracellular matrix forming a strong desmoplastic reaction, which is a hallmark of the disease. A complex cross-talk between tumor cells and the stroma exists with reciprocal influence that dictates tumor progression and ultimately the clinical outcome. In this context, tumor infiltrating immune cells through secretion of chemokine and cytokines exert an important regulatory role. Here we review the correlation between the immune infiltrates, evaluated on tumor samples of pancreatic cancer patients underwent surgical resection, and disease free and/or overall survival after surgery. Specifically, we focus on tumor infiltrating lymphocytes (TILs), mast cells (MCs) and macrophages that all contribute to a Th2-type inflammatory and immunosuppressive microenvironment. In these patients tumor immune infiltrates not only do not contribute to disease eradication but rather the features of Th2-type inflammation and immunosuppression is significantly associated with more rapid disease progression and reduced survival.

5 Article Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. 2011

De Monte, Lucia / Reni, Michele / Tassi, Elena / Clavenna, Daniela / Papa, Ilenia / Recalde, Helios / Braga, Marco / Di Carlo, Valerio / Doglioni, Claudio / Protti, Maria Pia. ·Tumor Immunology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. ·J Exp Med · Pubmed #21339327.

ABSTRACT: Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.