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Laetitia Douguet, Lloyd Bod, Renée Lengagne, Laura Labarthe, Masashi Kato, Marie-Françoise Avril, Armelle Prévost-Blondel
γδ T lymphocytes may exert either protective or tumor-promoting functions in cancer, mostly based on their polarization toward interferon (IFN)-γ or interleukin (IL)-17 productions, respectively. Here, we demonstrate that γδ T cells accelerate the spontaneous metastatic melanoma development in a model of transgenic mice for the human RET oncogene (Ret mice). We identify unanticipated roles of inducible nitric oxide synthase (NOS2) in favoring the recruitment of pro-tumor γδ T cells within the primary tumor...
August 2016: Oncoimmunology
Carl M Hay, Erin Sult, Qihui Huang, Kathy Mulgrew, Stacy R Fuhrmann, Kelly A McGlinchey, Scott A Hammond, Raymond Rothstein, Jonathan Rios-Doria, Edmund Poon, Nick Holoweckyj, Nicholas M Durham, Ching Ching Leow, Gundo Diedrich, Melissa Damschroder, Ronald Herbst, Robert E Hollingsworth, Kris F Sachsenmeier
MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models...
August 2016: Oncoimmunology
Zhenyu Xu, Jing Shen, Maggie Haitian Wang, Tao Yi, Yangyang Yu, Yinxin Zhu, Bo Chen, Jianping Chen, Longfei Li, Minxing Li, Jian Zuo, Hui Jiang, Dexi Zhou, Jiajie Luan, Zhangang Xiao
The B7 gene family has crucial roles in the regulation of adaptive cellular immunity. In cancer, deregulation of co-inhibitory B7 molecules is associated with reduced antitumor immunity and cancer immune evasion. FDA approval of cancer immunotherapy antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1)-both ligands of the B7 family-demonstrate the impact of these checkpoint regulators in cancer. Using data from cBioPortal, we performed comprehensive molecular profiling of the 10 currently known B7 family proteins in 105 different cancers...
August 2016: Oncoimmunology
Lauren M Habenicht, Tina C Albershardt, Brian M Iritani, Alanna Ruddell
Tumor-draining lymph nodes (TDLNs) often enlarge in human cancer patients and in murine tumor models, due to lymphocyte accumulation and lymphatic sinus growth. B lymphocytes within TDLNs can drive lymph node hypertrophy in response to tumor growth, however little is known about the mechanisms directing the preferential accumulation of B lymphocytes relative to T cells in enlarging TDLNs. To define why B and T lymphocytes accumulate in TDLNs, we quantified lymphocyte proliferation, apoptosis, entry, and exit in TDLNs versus contralateral non-TDLNs (NTDLNs) in a footpad B16-F10 melanoma mouse model...
August 2016: Oncoimmunology
Martin G Klatt, Daniel J Kowalewski, Heiko Schuster, Moreno Di Marco, Jörg Hennenlotter, Arnulf Stenzl, Hans-Georg Rammensee, Stefan Stevanović
Despite recent advances in immunotherapy of renal cell carcinoma (RCC), peptide vaccination strategies still lack an approach for personalized peptide vaccination that takes intra- and inter-tumoral heterogeneity and biological characteristics into account. In this study, we use an immunoprecipitation and mass spectrometry-based approach supplemented by network analysis of HLA ligands to target this goal. By analyzing HLA-presented peptides for HLA class I and II of 11 malignant and 6 non-malignant kidney tissue samples, more than 2,700 peptides and 1,600 corresponding source proteins were identified...
August 2016: Oncoimmunology
Marina Bacac, Christian Klein, Pablo Umana
Carcinoembryonic antigen T cell bispecific antibody (CEA TCB) is a bispecific antibody used to recognize CEA and CD3e via a novel molecular format (2:1) that induces T cell-mediated killing of CEA over-expressing tumors while sparing primary cells with low CEA expression. CEA TCB treatment inhibits tumor growth and generates a highly inflamed tumor microenvironment.
August 2016: Oncoimmunology
Shamaila Munir Ahmad, Evelina Martinenaite, Morten Hansen, Niels Junker, Troels Holz Borch, Özcan Met, Marco Donia, Inge Marie Svane, Mads Hald Andersen
We recently described naturally occurring PD-L1-specific T cells that recognize PD-L1-expressing immune cells as well as malignant cells. In the present study, we investigated whether the immunogenicity of a dendritic cell (DC)-based vaccine could be influenced by co-stimulation with a known PD-L1-derived epitope. We incubated a PD-L1-derived peptide epitope (19 amino acids long) or a control peptide (an irrelevant HIV epitope) with peripheral blood mononuclear cells from patients with malignant melanoma who had received a DC-based vaccine...
August 2016: Oncoimmunology
Djoke Hendriks, Yuan He, Iris Koopmans, Valerie R Wiersma, Robert J van Ginkel, Douwe F Samplonius, Wijnand Helfrich, Edwin Bremer
Antibodies that block PD-L1/PD-1 immune checkpoints restore the activity of functionally-impaired antitumor T cells. These antibodies show unprecedented clinical benefit in various advanced cancers, particularly in melanoma. However, only a subset of cancer patients responds to current PD-L1/PD-1-blocking strategies, highlighting the need for further advancements in PD-L1/PD-1-based immunotherapy. Here, we report on a novel approach designed to combine PD-L1 checkpoint inhibition with the tumor-selective induction of apoptosis by TNF-related Apoptosis Inducing Ligand (TRAIL)...
August 2016: Oncoimmunology
Steve Boudewijns, Rutger H T Koornstra, Harm Westdorp, Gerty Schreibelt, Alfons J M van den Eertwegh, Marnix H Geukes Foppen, John B Haanen, I Jolanda M de Vries, Carl G Figdor, Kalijn F Bol, Winald R Gerritsen
BACKGROUND: Ipilimumab has proven to be effective in metastatic melanoma patients. The purpose of this study was to determine the efficacy of ipilimumab in advanced melanoma patients who showed progressive disease upon experimental dendritic cell (DC) vaccination. METHODS: Retrospective analysis of 48 stage IV melanoma patients treated with ipilimumab after progression upon DC vaccination earlier in their treatment. DC vaccination was given either as adjuvant treatment for stage III disease (n = 18) or for stage IV disease (n = 30)...
August 2016: Oncoimmunology
Amir A Al-Khami, Paulo C Rodriguez, Augusto C Ochoa
MDSC undergo metabolic reprogramming in the tumor resulting in an increased fatty acid β oxidation that supports their immunosuppressive functions. Fatty acid oxidation inhibitors, used to treat coronary disease, significantly delayed tumor growth and had a significantly increased antitumor effect when combined with adoptive cell therapy or low dose chemotherapy.
August 2016: Oncoimmunology
Elisa Cappuzzello, Anna Tosi, Paola Zanovello, Roberta Sommaggio, Antonio Rosato
Cytokine-induced Killer (CIK) cells are a heterogeneous population of ex vivo expanded T lymphocytes capable of MHC-unrestricted antitumor activity, which share phenotypic and functional features with both NK and T cells. Preclinical data and initial clinical studies demonstrated their high tolerability in vivo, supporting CIK cells as a promising cell population for adoptive cell immunotherapy. In this study, we report for the first time that CIK cells display a donor-dependent expression of CD16, which can be engaged by trastuzumab or cetuximab to exert a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian and breast cancer cell lines, leading to an increased lytic activity in vitro, and an enhanced therapeutic efficacy in vivo...
August 2016: Oncoimmunology
Lauren V Wood, Antonio Fojo, Brenda D Roberson, Meghan S B Hughes, William Dahut, James L Gulley, Ravi A Madan, Philip M Arlen, Marianna Sabatino, David F Stroncek, Luciano Castiello, Jane B Trepel, Min-Jung Lee, Howard L Parnes, Seth M Steinberg, Masaki Terabe, Julia Wilkerson, Ira Pastan, Jay A Berzofsky
T-cell receptor alternate reading frame protein (TARP) is a 58-residue protein over-expressed in prostate and breast cancer. We investigated TARP peptide vaccination's impact on the rise in PSA (expressed as Slope Log(PSA) or PSA Doubling Time (PSADT)), validated tumor growth measures, and tumor growth rate in men with Stage D0 prostate cancer. HLA-A*0201 positive men were randomized to receive epitope-enhanced (29-37-9V) and wild-type (27-35) TARP peptides administered as a Montanide/GM-CSF peptide emulsion or as an autologous peptide-pulsed dendritic cell vaccine every 3 weeks for a total of five vaccinations with an optional 6th dose of vaccine at 36 weeks based on immune response or PSADT criteria with a booster dose of vaccine for all patients at 48 and 96 weeks...
August 2016: Oncoimmunology
Erik Ladomersky, Matthew Genet, Lijie Zhai, Galina Gritsina, Kristen L Lauing, Rishi R Lulla, Jason Fangusaro, Alicia Lenzen, Priya Kumthekar, Jeffrey J Raizer, David C Binder, C David James, Derek A Wainwright
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored...
August 2016: Oncoimmunology
Marcos Vasquez, Jessica Fioravanti, Fernando Aranda, Vladimir Paredes, Celia Gomar, Nuria Ardaiz, Veronica Fernandez-Ruiz, Miriam Méndez, Estanislao Nistal-Villan, Esther Larrea, Qinshan Gao, Gloria Gonzalez-Aseguinolaza, Jesus Prieto, Pedro Berraondo
Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies...
August 2016: Oncoimmunology
Conor J Kearney, Kelly M Ramsbottom, Ilia Voskoboinik, Phillip K Darcy, Jane Oliaro
Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit...
August 2016: Oncoimmunology
Stefania Di Blasio, Inge M N Wortel, Diede A G van Bladel, Laura E de Vries, Tjitske Duiveman-de Boer, Kuntal Worah, Nienke de Haas, Sonja I Buschow, I Jolanda M de Vries, Carl G Figdor, Stanleyson V Hato
Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1)...
August 2016: Oncoimmunology
Hweixian Leong Penny, Je Lin Sieow, Giulia Adriani, Wei Hseun Yeap, Peter See Chi Ee, Boris San Luis, Bernett Lee, Terence Lee, Shi Ya Mak, Ying Swan Ho, Kong Peng Lam, Choon Kiat Ong, Ruby Y J Huang, Florent Ginhoux, Olaf Rotzschke, Roger D Kamm, Siew Cheng Wong
Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth...
August 2016: Oncoimmunology
Bisweswar Nandi, Mia Shapiro, Mehmet K Samur, Christine Pai, Natasha Y Frank, Charles Yoon, Rao H Prabhala, Nikhil C Munshi, Jason S Gold
Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers...
August 2016: Oncoimmunology
Masahiro Azuma, Yohei Takeda, Hiroko Nakajima, Haruo Sugiyama, Takashi Ebihara, Hiroyuki Oshiumi, Misako Matsumoto, Tsukasa Seya
Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells...
August 2016: Oncoimmunology
Dallas B Flies, Tomoe Higuchi, Jaryse C Harris, Vibha Jha, Phyllis A Gimotty, Sarah F Adams
Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment...
August 2016: Oncoimmunology
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