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Laetitia Douguet, Lloyd Bod, Laura Labarthe, Renée Lengagne, Masashi Kato, Isabelle Couillin, Armelle Prévost-Blondel
The high expression of inducible nitric oxide synthase (NOS2) by myeloid-derived suppressor cells (MDSCs) is a key mechanism of immune evasion in cancer. Recently we reported that NOS2 is also expressed by γδ T cells in melanoma, contributing to their polarization towards a pro-tumor phenotype. The molecular mechanisms underlying regulation of NOS2 expression in tumor-induced γδ T cells remain unexplored. By using the model of mice transgenic for the ret oncogene (Ret mice) that develops a spontaneous metastatic melanoma, we evidence that interleukin (IL)-1β and IL-6 drive NOS2 expression in γδ T cells...
2018: Oncoimmunology
Abraham G Lin, Bo Xiang, Dante J Merlino, Trevor R Baybutt, Joya Sahu, Alexander Fridman, Adam E Snook, Vandana Miller
Immunogenic cell death is characterized by the emission of danger signals that facilitate activation of an adaptive immune response against dead-cell antigens. In the case of cancer therapy, tumor cells undergoing immunogenic death promote cancer-specific immunity. Identification, characterization, and optimization of stimuli that induce immunogenic cancer cell death has tremendous potential to improve the outcomes of cancer therapy. In this study, we show that non-thermal, atmospheric pressure plasma can be operated to induce immunogenic cell death in an animal model of colorectal cancer...
2018: Oncoimmunology
Priscilla S Redd, Chunwan Lu, John D Klement, Mohammed L Ibrahim, Gang Zhou, Takumi Kumai, Esteban Celis, Kebin Liu
PD-1 is a co-repressive receptor that curbs T cell activation and thereby serves as a protection mechanism against autoimmunity under physiological conditions. Under pathological conditions, tumor cells express PD-L1 as an adaptive resistant mechanism to suppress PD-1+ T cells to evade host immunosurveillance. PD-1 therefore is a key target in cancer immunotherapy. Despite the extensive studies of PD-1 expression regulation, the pdcd1 transcription machinery and regulatory mechanisms are still not fully understood...
2018: Oncoimmunology
Michaela C Baldauf, Julia S Gerke, Andreas Kirschner, Franziska Blaeschke, Manuel Effenberger, Kilian Schober, Rebeca Alba Rubio, Takayuki Kanaseki, Merve M Kiran, Marlene Dallmayer, Julian Musa, Nurset Akpolat, Ayse N Akatli, Fernando C Rosman, Özlem Özen, Shintaro Sugita, Tadashi Hasegawa, Haruhiko Sugimura, Daniel Baumhoer, Maximilian M L Knott, Giuseppina Sannino, Aruna Marchetto, Jing Li, Dirk H Busch, Tobias Feuchtinger, Shunya Ohmura, Martin F Orth, Uwe Thiel, Thomas Kirchner, Thomas G P Grünewald
Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Immunogenic peptides encoded by cancer-specific genes (CSGs) may enable targeted immunotherapy, even of oligo-mutated cancers, which lack neo-antigens generated by protein-coding missense mutations. Here, we describe an algorithm and user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues) that automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from transcriptome data...
2018: Oncoimmunology
Robert E Jordan, Xuejun Fan, Georgina Salazar, Ningyan Zhang, Zhiqiang An
The host immune system adopts multiple mechanisms involving antibodies to confront cancer cells. Accordingly, anti-tumor mAbs have become mainstays in cancer treatment. However, neither host immunity nor mAb therapies appear capable of controlling tumor growth in all cases. Structural instability of IgG was overlooked as a factor contributing to immunosuppression in the tumor microenvironment. Recently, physiological proteinases were identified that disable IgG immune effector functions. Evidence shows that these proteinases cause localized IgG impairment by selective cleavage of a single IgG peptide bond in the hinge-region...
2018: Oncoimmunology
Huseyin Atakan Ekiz, Shu-Chin Alicia Lai, Harika Gundlapalli, Fadi Haroun, Matthew A Williams, Alana L Welm
The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors...
2018: Oncoimmunology
Ji-Won Jung, Margaret Veitch, Jennifer A Bridge, Nana H Overgaard, Jazmina L Cruz, Richard Linedale, Michael E Franklin, Nicholas A Saunders, Fiona Simpson, Ian H Frazer, Raymond J Steptoe, James W Wells
Patients receiving immunosuppressive drugs to prevent organ transplant rejection exhibit a greatly increased risk of developing cutaneous squamous cell carcinoma (SCC). However, not all immunosuppressive drugs confer the same risk. Randomised, controlled trials demonstrate that switching renal transplant recipients receiving calcineurin inhibitor-based therapies to mammalian target of rapamycin (mTOR) inhibitors results in a reduced incidence of de novo SSC formation, and can even result in the regression of pre-existing premalignant lesions...
2018: Oncoimmunology
Christopher Larson, Bryan Oronsky, Gina Varner, Scott Caroen, Erica Burbano, Elisa Insel, Farah Hedjran, Corey A Carter, Tony R Reid
The aim of this review is to provide practical information on the handling, storage, and administration procedures for personalized oncolytic adenoviruses (PTAVs), which have recently entered clinical trials. As described herein, personalized oncolytic viruses refer to transcriptionally attenuated (TA) type 5 adenoviruses that are engineered to carry one or more neoantigenic transgenes derived from patient tumors. Vials of personalized viruses should be stored at -60°C without refreezing after thawing to maintain infectivity...
2018: Oncoimmunology
Belen Lopez-Millan, Rafael Diaz de la Guardia, Heleia Roca-Ho, Eduardo Anguita, Abul B M M K Islam, Damia Romero-Moya, Cristina Prieto, Francisco Gutierrez-Agüera, Jose Antonio Bejarano-Garcia, Jose Antonio Perez-Simon, Paula Costales, Montse Rovira, Pedro Marín, Silvia Menendez, Mar Iglesias, Jose Luis Fuster, Alvaro Urbano-Ispizua, Fernando Anjos-Afonso, Clara Bueno, Pablo Menendez
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma...
2018: Oncoimmunology
Chia-Jen Wu, Yi-Ting Tsai, I-Jung Lee, Ping-Yi Wu, Long-Sheng Lu, Wen-Shan Tsao, Yi-Jou Huang, Ching-Cheng Chang, Shuk-Man Ka, Mi-Hua Tao
Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities...
2018: Oncoimmunology
Florian Bochen, Benedikt Balensiefer, Sandrina Körner, Jörg Thomas Bittenbring, Frank Neumann, Armand Koch, Klaus Bumm, Anke Marx, Silke Wemmert, Georgios Papaspyrou, David Zuschlag, Jan Philipp Kühn, Basel Al Kadah, Bernhard Schick, Maximilian Linxweiler
Vitamin D deficiency is frequently observed in human cancer patients and a prognostic relevance could be shown for some entities. Additionally, it is known that vitamin D can stimulate the patients' antitumor immunity. However, valid epidemiological data for head and neck squamous cell carcinoma (HNSCC) patients are sparse and functional studies on a possible connection between vitamin D and the patients' immune system are missing. 25-OH vitamin D serum levels were analyzed in 231 HNSCC patients and 232 healthy controls and correlated with clinical data and patient survival...
2018: Oncoimmunology
Michael Poch, MacLean Hall, Autumn Joerger, Krithika Kodumudi, Matthew Beatty, Pasquale P Innamarato, Brittany L Bunch, Mayer N Fishman, Jingsong Zhang, Wade J Sexton, Julio M Pow-Sang, Scott M Gilbert, Philippe E Spiess, Jasreman Dhillon, Linda Kelley, John Mullinax, Amod A Sarnaik, Shari Pilon-Thomas
Advanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks...
2018: Oncoimmunology
Thomas J Kandl, Oded Sagiv, Jonathan L Curry, Jing Ning, Junsheng Ma, Courtney W Hudgens, John Van Arnam, Jennifer A Wargo, Bita Esmaeli, Michael T Tetzlaff
Ocular adnexal sebaceous carcinoma (OASC) is an aggressive malignancy that frequently recurs locally and metastasizes. Surgical extirpation may produce significant aesthetic morbidity, and effective systemic therapies for locally advanced or metastatic disease are largely ineffective. Immune checkpoint inhibitors have shown efficacy in the management of several solid tumors where tumor cell PD-L1 expression correlates with improved response. To determine whether OASC might be amenable to immune checkpoint blockade, we performed comprehensive immune profiling for CD3, CD8, PD-1, FOXP3, and PD-L1 in 24 patients with primary OASC...
2018: Oncoimmunology
Nicolas Isambert, Alice Hervieu, Cedric Rébé, Audrey Hennequin, Christophe Borg, Sylvie Zanetta, Angélique Chevriaux, Corentin Richard, Valentin Derangère, Emeric Limagne, Julie Blanc, Aurélie Bertaut, François Ghiringhelli
In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy. Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS )...
2018: Oncoimmunology
Todd A Braciak, Claudia C Roskopf, Sarah Wildenhain, Nadja C Fenn, Christian B Schiller, Ingo A Schubert, Uwe Jacob, Annemarie Honegger, Christina Krupka, Marion Subklewe, Karsten Spiekermann, Karl-Peter Hopfner, Georg H Fey, Michael Aigner, Stefan Krause, Andreas Mackensen, Fuat S Oduncu
A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents...
2018: Oncoimmunology
Sina Fellermeier-Kopf, Friederike Gieseke, Ugur Sahin, Dafne Müller, Klaus Pfizenmaier, Roland E Kontermann
Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell - antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines)...
2018: Oncoimmunology
Silvia Gaggero, Maurizio Bruschi, Andrea Petretto, Monica Parodi, Genny Del Zotto, Chiara Lavarello, Carola Prato, Laura Santucci, Alessandra Barbuto, Cristina Bottino, Giovanni Candiano, Alessandro Moretta, Massimo Vitale, Lorenzo Moretta, Claudia Cantoni
The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 regulates NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. In particular, it also modulates IFN-γ production induced by Platelet-Derived Growth Factor (PDGF)-DD following NKp44 engagement...
2018: Oncoimmunology
Julie G Grossman, Timothy M Nywening, Brian A Belt, Roheena Z Panni, Bradley A Krasnick, David G DeNardo, William G Hawkins, S Peter Goedegebuure, David C Linehan, Ryan C Fields
The tumor microenvironment (TME) represents a significant barrier to creating effective therapies for metastatic colorectal cancer (mCRC). In several malignancies, bone marrow derived CCR2+ inflammatory monocytes (IM) are recruited to the TME by neoplastic cells, where they become immunosuppressive tumor associated macrophages (TAM). Here we report that mCRC expression of the chemokine CCL2 facilitates recruitment of CCR2+ IM from the bone marrow to the peripheral blood. Immune monitoring of circulating monocytes in patients with mCRC found this influx was a prognostic biomarker and correlated with worse clinical outcomes...
2018: Oncoimmunology
Liru Wang, Bei Jia, David F Claxton, W Christopher Ehmann, Witold B Rybka, Shin Mineishi, Seema Naik, Muhammad R Khawaja, Jeff Sivik, Junyan Han, Raymond J Hohl, Hong Zheng
Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients...
2018: Oncoimmunology
Mia Aaboe Jørgensen, Morten Orebo Holmström, Evelina Martinenaite, Caroline Hasselbalch Riley, Hans Carl Hasselbalch, Mads Hald Andersen
Compelling evidence supports the existence of a profound immune dysregulation in patients with chronic myeloproliferative neoplasms (MPN). Increased Arginase-1 expression has been described in MPN patients and in solid cancers. This increase contributes to an immunosuppressive tumor microenvironment in MPN patients because of L-arginine depletion by Arginase-1-expressing regulatory cells and cancer cells, which subsequently limits the activation of circulating effector cells. In the present study, we demonstrate that Arginase-1-derived peptides are recognized by T cells among peripheral mononuclear blood cells from MPN patients...
2018: Oncoimmunology
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