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Pancreatic cancer,CD4,CD8

Christoph M Griessinger, Andreas M Schmid, Dominik Sonanini, Barbara F Schörg, Mohamed Ali Jarboui, Daniel Bukala, Natalie Mucha, Birgit Fehrenbacher, Julia Steinhilber, Manuela Martella, Ursula Kohlhofer, Martin Schaller, Lars Zender, Hans-Georg Rammensee, Leticia Quintanilla-Martinez, Martin Röcken, Manfred Kneilling, Bernd J Pichler
Cancer treatment with adoptively transferred tumor-associated antigen-specific CD4+ T-helper cells is a promising immunotherapeutic approach. In the pancreatic cancer model RIP-Tag2, the intraperitoneal (i.p.) application of Tag-specific TH1 cells exhibited a profound antitumoral efficiency. We investigated, whether an intravenous (i.v.) application of Tag-TH1 cells induces an equivalent therapeutic effect. Adoptively transferred fluorescent Tag-TH1 cells revealed a pronounced homing to the tumors after either i...
February 7, 2019: Carcinogenesis
Eriko Katsuta, Qianya Qi, Xuan Peng, Steven N Hochwald, Li Yan, Kazuaki Takabe
Pancreatic ductal adenocarcinoma (PDAC) is known for its hypovascularity. Bevacizumab, an anti-angiogenic drug, added to standard chemotherapy demonstrated no improvement in outcome for PDAC. Therefore, we hypothesized that increased vascularity may be associated with improved outcomes in PDAC possibly due to better delivery of tumor specific immune cells. To test this hypothesis, PDAC patients were classified into either high or low CD31 expression groups utilizing mRNA expression from RNA-sequence data in The Cancer Genome Atlas (TCGA) pancreatic cancer cohort...
February 4, 2019: Scientific Reports
Ligia I Bastea, Geou-Yarh Liou, Veethika Pandey, Alicia K Fleming, Christina A Von Roemeling, Heike Doeppler, Zhimin Li, Yushi Qiu, Brandy Edenfield, John A Copland, Han W Tun, Peter Storz
During development of pancreatic cancer, alternatively-activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively-activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4 (IRF4), a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively-activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL-1α and presence of activated (IFNγ positive) CD4+ and CD8+ T cell populations...
January 29, 2019: Cancer Research
Yoshio Sakai, Masaki Miyazawa, Takuya Komura, Takeshi Yamada, Alessandro Nasti, Keiko Yoshida, Hisashi Takabatake, Masatoshi Yamato, Taro Yamashita, Tatsuya Yamashita, Eishiro Mizukoshi, Mai Okuzono, Tuyen Thuy Bich Ho, Kazunori Kawaguchi, Takashi Wada, Masao Honda, Shuichi Kaneko
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti-tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr-1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells...
January 18, 2019: Cancer Science
Jorge Blando, Anu Sharma, Maria Gisela Higa, Hao Zhao, Luis Vence, Shalini S Yadav, Jiseong Kim, Alejandro M Sepulveda, Michael Sharp, Anirban Maitra, Jennifer Wargo, Michael Tetzlaff, Russell Broaddus, Matthew H G Katz, Gauri R Varadhachary, Michael Overman, Huamin Wang, Cassian Yee, Chantale Bernatchez, Christine Iacobuzio-Donahue, Sreyashi Basu, James P Allison, Padmanee Sharma
Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67)...
January 11, 2019: Proceedings of the National Academy of Sciences of the United States of America
Can Cui, Xiuyun Tian, Jianhui Wu, Chaoting Zhang, Qin Tan, Xiaoya Guan, Bin Dong, Min Zhao, Zheming Lu, Chunyi Hao
Pancreatic cancer is lethal due to lack of perceptible symptoms and effective treatment methods. Immunotherapy may provide promising therapeutic choices for malignant tumors like pancreatic cancer. Tumor infiltrating lymphocytes (TILs) in tumor mesenchyme could recognize peptide antigens presented on the surface of tumor cells. This study aimed to test the relationship between the TCR β repertoire of the tumor and peripheral blood, and also to investigate the intra-tumor spatial heterogeneity of the TCR β repertoire in pancreatic cancer...
November 13, 2018: Cancer Science
May Tun Saung, Stephen Muth, Ding Ding, Dwayne L Thomas, Alex B Blair, Takahiro Tsujikawa, Lisa Coussens, Elizabeth M Jaffee, Lei Zheng
BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/αPD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/αPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated...
November 13, 2018: Journal for Immunotherapy of Cancer
Jordan Aldersley, David R Lorenz, Vikas Misra, Hajime Uno, Dana Gabuzda
OBJECTIVE(S): HIV-positive individuals have elevated rates of anal squamous cell carcinoma (SCC), and sexually transmitted infections with its causative agent, high-risk human papillomavirus, and other oncoviruses including hepatitis B virus (HBV). HBV infection can cause liver cancer, and has been associated with increased risk of some extra-hepatic cancers including biliary tract cancer, pancreatic cancer, and non-Hodgkin lymphoma. Whether HBV is associated with anal SCC risk is unknown...
January 27, 2019: AIDS
Felicitas Rataj, Fabian B T Kraus, Michael Chaloupka, Simon Grassmann, Constanze Heise, Bruno L Cadilha, Peter Duewell, Stefan Endres, Sebastian Kobold
Background: Interaction of the programmed death receptor 1 (PD-1) and its ligand, PD-L1, suppresses T cell activity and permits tumors to evade T cell-mediated immune surveillance. We have recently demonstrated that antigen-specific CD8+ T cells transduced with a PD1-CD28 fusion protein are protected from PD-1-mediated inhibition. We have now investigated the potential of PD1-CD28 fusion protein-transduced CD4+ T cells alone or in combination with CD8+ T cells for immunotherapy of pancreatic cancer and non-Hodgkin lymphoma...
2018: Frontiers in Immunology
Ning Pu, Guochao Zhao, Shanshan Gao, Yutong Cui, Yadong Xu, Yang Lv, Abulimiti Nuerxiati, Wenchuan Wu
Previous fundamental or clinical trials of dendritic cell (DC) vaccine against pancreatic ductal adenocarcinoma (PDAC) revealed the burgeoning neoadjuvant immunotherapy. Microarray studies indicated that multiple ingredients of the transfer growth factor beta (TGF-β) pathway were overexpressed in PDAC, which inhibited the intratumoral immune response. To explore whether the DC volume in tumor microenvironment contributes to the differentiation of T cell cohort and test the hypothesis that combining DC vaccine with TGF-β inhibitors will elevate the anti-tumor immune response, we managed to co-culture T cells in vitro with pancreatic cancer cells and DCs in different concentrations, and combine TGF-β blockage with DC vaccine therapy in a murine model of pancreatic cancer...
2018: Central-European Journal of Immunology
Ujjwal Mukund Mahajan, Eno Langhoff, Elisabetta Goni, Eithne Costello, William Greenhalf, Christopher Halloran, Steffen Ormanns, Stephan Kruger, Stefan Boeck, Silvia Ribback, Georg Beyer, Frank Dombroswki, Frank-Ulrich Weiss, John P Neoptolemos, Jens Werner, Jan G D'Haese, Alexandr Bazhin, Julian Peterhansl, Svenja Pichlmeier, Markus W Büchler, Jörg Kleeff, Paula Ganeh, Matthias Sendler, Daniel H Palmer, Thomas Kohlmann, Roland Rad, Ivonne Regel, Markus M Lerch, Julia Mayerle
BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils...
November 2018: Gastroenterology
Mayura V Wagle, Julia M Marchingo, Jason Howitt, Seong-Seng Tan, Christopher C Goodnow, Ian A Parish
Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice...
July 17, 2018: Cell Reports
Bhalchandra Mirlekar, Daniel Michaud, Ryan Searcy, Kevin Greene, Yuliya Pylayeva-Gupta
Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced...
September 2018: Cancer Immunology Research
Giovanni Lo Re, Francesco Lo Re, Paolo Doretto, Alessandro Del Conte, Maria Amadio, Cinzia Cozzi, Maria Maddalena Casarotto, Daniele Maruzzi, Wally Marus, Paolo Ubiali, Paolo Sandri
BACKGROUND: Immune tolerance seems to correlate with disease progression and T regulatory cells (Tregs) and myeloid-derived suppressor cells play a relevant role in immunosuppression. Cyclophosphamide (Cyt) and Fluorouracil (FU) seem to reduce these cell populations. METHODS AND OBJECTIVE: Establishing safety, feasibility, activity and impact on the immune system (neutrophil/lymphocyte [N/L], platelet/L [Plt/L], monocyte [M] and lymphocyte subpopulation (CD3, CD4, CD8, CD16, HLADR/CD3, Tregs, cells count), CD8/Treg and C-reactive protein (CRP)...
June 26, 2018: Cytokine
John D Lyons, Ching-Wen Chen, Zhe Liang, Wenxiao Zhang, Deena B Chihade, Eileen M Burd, Alton B Farris, Mandy L Ford, Craig M Coopersmith
Patients with cancer who develop sepsis have a markedly higher mortality than patients who were healthy prior to the onset of sepsis. Potential mechanisms underlying this difference have previously been examined in two preclinical models of cancer followed by sepsis. Both pancreatic cancer/pneumonia and lung cancer/cecal ligation and puncture (CLP) increase murine mortality, associated with alterations in lymphocyte apoptosis and intestinal integrity. However, pancreatic cancer/pneumonia decreases lymphocyte apoptosis and increases gut apoptosis while lung cancer/CLP increases lymphocyte apoptosis and decreases intestinal proliferation...
June 20, 2018: Shock
Martin Wartenberg, Silvia Cibin, Inti Zlobec, Erik Vassella, Serenella Eppenberger-Castori, Luigi Terracciano, Micha David Eichmann, Mathias Worni, Beat Gloor, Aurel Perren, Eva Karamitopoulou
Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. Experimental Design: A well-characterized PDAC cohort ( n = 110) underwent next-generation sequencing with a hot spot cancer panel while next-generation tissue microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM), and DNA mismatch repair proteins...
September 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W Herzog, Brian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R Balfour Sartor, Deepak Saxena, George Miller
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation...
April 2018: Cancer Discovery
Alessandro Giardino, Giulio Innamorati, Stefano Ugel, Omar Perbellini, Roberto Girelli, Isabella Frigerio, Paolo Regi, Filippo Scopelliti, Giovanni Butturini, Salvatore Paiella, Matilde Bacchion, Claudio Bassi
OBJECTIVE/BACKGROUND: RFA of pancreatic cancer has been demonstrated to be feasible and safe with a positive impact on survival. The aim was to investigate whether an immune reaction is activated after locally advanced pancreatic cancer (LAPC) ablation. METHODS: Peripheral Blood samples were obtained preoperatively and on post-operative days 3-30. Evaluated parameters were: cells [CD4+ , CD8+ and activated subsets, T-Reg, Monocytes, myeloid and plasmocytoid Dendritic cells (mDC and pDC)] and cytokines [Interleukin (IL)-6, Stromal-cells derived factor (SDF)-1, IL-1β, Tumour-Necrosis Factor (TNF)-α, Interferon (IFN)-γ, Vascular Endothelial Growth Factor (VEGF), chemokine (C-C motif) ligand 5 (CCL-5), Transforming-Growth Factor (TGF)-β]...
November 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Cuicui Lang, Jinyan Wang, Lei Chen
The tumor-associated immune response is governed by the signalling events of various regulatory molecules, one of which is the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). In conventional T cells, CTLA-4 could outcompete CD28 in binding to CD80/86 but does not produce a co-stimulatory signal, resulting in T cell anergy. CTLA-4 in regulatory T cells (Tregs) could also function in a cell-extrinsic fashion by removing CD80/CD86 from the antigen-presenting cells (APCs), thus preventing further priming of other T cells...
November 15, 2017: Experimental Cell Research
Fee Bengsch, Dawson M Knoblock, Anni Liu, Florencia McAllister, Gregory L Beatty
The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications...
December 2017: Cancer Immunology, Immunotherapy: CII
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