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A M Gravett, N Trautwein, S Stevanović, A G Dalgleish, J Copier
The antigenic makeup of tumour cells can have a profound effect on the progression of cancer and success of immunotherapies. Therefore, one strategy to improve the efficacy of cancer treatments is to augment the antigens displayed by tumours. The present study explores how the recognition of tumour cells may be altered by non-cytotoxic concentrations of gemcitabine (GEM). Testing a panel of chemotherapeutics in human cancer cell lines in vitro , it was found that GEM increased surface expression of HLA-A,B,C and that underlying this were specific increases in β-2-microglobulin and immunoproteasome subunit proteins...
2018: Oncoimmunology
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[This corrects the article DOI: 10.1080/2162402X.2017.1356144.].
2018: Oncoimmunology
Guoying Zhou, Lisanne Noordam, Dave Sprengers, Michail Doukas, Patrick P C Boor, Adriaan A van Beek, Remco Erkens, Shanta Mancham, Dirk Grünhagen, Anand G Menon, Johan F Lange, Pim J W A Burger, Alexandra Brandt, Boris Galjart, Cornelis Verhoef, Jaap Kwekkeboom, Marco J Bruno
Purpose : Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology : Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC...
2018: Oncoimmunology
Jieke Cui, Qing Li, Mei Luo, Zhaodong Zhong, Shu Zhou, Lin Jiang, Na Shen, Zhe Geng, Hui Cheng, Li Meng, Shujuan Yi, Hui Sun, Feifei Wu, Zunmin Zhu, Ping Zou, Yong You, An-Yuan Guo, Xiaojian Zhu
T cell function in cancer patients is usually impaired due to the constitutive activation of immune checkpoint inhibitors. This state is known as 'exhaustion' and is often associated with the inefficient control of tumors or persistent infections. In this work, we investigated the role of leukemia cell-derived microvesicles (MVs) in T cell exhaustion. Following incubation with MVs from various sources, all T cell subtypes exhibited the exhaustion phonotype and impaired cytokine secretion in vitro. Mice models also showed the connection between immune checkpoint inhibitors and MV injection...
2018: Oncoimmunology
Joseph DiDomenico, Jonathan B Lamano, Daniel Oyon, Yuping Li, Dorina Veliceasa, Gurvinder Kaur, Leonel Ampie, Winward Choy, Jason B Lamano, Orin Bloch
Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance...
2018: Oncoimmunology
Feng-Ying Huang, Jing Lei, Yan Sun, Fei Yan, Bin Chen, Liming Zhang, Zhuoxuan Lu, Rong Cao, Ying-Ying Lin, Cai-Chun Wang, Guang-Hong Tan
Immunogenic cell death (ICD) is a specific kind of cell death that stimulates the immune system to combat cancer cells. Ultrasound (US)-controlled targeted release of drugs by liposome-microbubble complexes is a promising approach due to its non-invasive nature and visibility through ultrasound imaging. However, it is not known whether this approach can enhance ICD induced by drugs, such as doxorubicin. Herein, we prepared a doxorubicin-liposome-microbubble complex (MbDox), and the resultant MbDox was then characterized and tested for US-controlled release of Dox (MbDox+US treatment) to enhance the induction of ICD in LL/2 and CT26 cancer cells and in syngeneic murine models...
2018: Oncoimmunology
M Xipell, I Victoria, V Hoffmann, J Villarreal, A García-Herrera, O Reig, L Rodas, M Blasco, E Poch, B Mellado, L F Quintana
Direct stimulation of the antitumor activity of immune system through checkpoint inhibitors (ICIs) has demonstrated efficacy in the treatment of different cancer types. The activity of these antibodies takes place in the immunological synapse blocking the binding of the negative immunoregulatory proteins, thus leading to the finalization of the immune response. Despite having a favorable toxicity profile, its mechanism of action impedes the negative regulation of the immune activity which can potentially favor autoimmune attacks to normal tissues...
2018: Oncoimmunology
Anna F Piotrowski, Thomas R Nirschl, Esteban Velarde, Lee Blosser, Sudipto Ganguly, Kathleen H Burns, Leo Luznik, John Wong, Charles G Drake, Stuart A Grossman
Severe radiation-related lymphopenia is common and associated with decreased survival in patients with several solid tumors. As the mechanisms underlying systemic lymphopenia are poorly understood, we developed an animal model to study the effects of brain radiation on lymphocytes and cytokines. C57 BL/6 and BALB/c mice received focal brain irradiation (4 Gy x 10 fractions or 2 Gy x 30 fractions). Weekly total lymphocyte counts (TLC), lymphocyte subsets and cytokines in blood and lymph nodes were measured...
2018: Oncoimmunology
Heidi Harjunpää, Stephen J Blake, Elizabeth Ahern, Stacey Allen, Jing Liu, Juming Yan, Viviana Lutzky, Kazuyoshi Takeda, Amy Roman Aguilera, Camille Guillerey, Deepak Mittal, Xian Yang Li, William C Dougall, Mark J Smyth, Michele W L Teng
Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination...
2018: Oncoimmunology
Matthew J Atherton, Kyle B Stephenson, Fanny Tzelepis, David Bakhshinyan, Jake K Nikota, Hwan Hee Son, Anna Jirovec, Charles Lefebvre, Anna Dvorkin-Gheva, Ali A Ashkar, Yonghong Wan, David F Stojdl, Eric C Belanger, Rodney H Breau, John C Bell, Fred Saad, Sheila K Singh, Jean-Simone Diallo, Brian D Lichty
Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo . An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance...
2018: Oncoimmunology
Víctor A Arrieta, Bernardo Cacho-Díaz, Junfei Zhao, Raul Rabadan, Li Chen, Adam M Sonabend
The relationship between anti-tumoral immunity and cancer progression is complex. Recently, immune editing has emerged as a model to explain the interplay between the immune system and the selection of genetic alterations in cancer. In this model, the immune system selects cancer cells that grow as these are fit to escape immune surveillance during tumor development. Gliomas and glioblastoma, the most aggressive and most common of all primary malignant brain tumors are genetically heterogeneous, are relatively less antigenic, and are less responsive to immunotherapy than other cancers...
2018: Oncoimmunology
Mareike Grees, Adi Sharbi-Yunger, Christos Evangelou, Daniel Baumann, Gal Cafri, Esther Tzehoval, Stefan B Eichmüller, Rienk Offringa, Jochen Utikal, Lea Eisenbach, Viktor Umansky
Despite melanoma immunogenicity and remarkable therapeutic effects of negative immune checkpoint inhibitors, a significant fraction of patients does not respond to current treatments. This could be due to limitations in tumor immunogenicity and profound immunosuppression in the melanoma microenvironment. Moreover, insufficient tumor antigen processing and presentation by dendritic cells (DC) may hamper the development of tumor-specific T cells. Using two genetically engineered mouse melanoma models ( RET and BRAFV600E transgenic mice), in which checkpoint inhibitor therapy alone is not efficacious, we performed proof-of-concept studies with an improved, multivalent DC vaccination strategy based on our recently developed genetic mRNA cancer vaccines...
2018: Oncoimmunology
Martin Böttcher, Kathrin Renner, Raffaela Berger, Kristin Mentz, Simone Thomas, Zugey Elizabeth Cardenas-Conejo, Katja Dettmer, Peter J Oefner, Andreas Mackensen, Marina Kreutz, Dimitrios Mougiakakos
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion...
2018: Oncoimmunology
Mine Ozcan, Jonas Janikovits, Magnus von Knebel Doeberitz, Matthias Kloor
Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation...
2018: Oncoimmunology
Olga Kuchuk, Alessandra Tuccitto, Davide Citterio, Veronica Huber, Chiara Camisaschi, Massimo Milione, Barbara Vergani, Antonello Villa, Malcolm Ronald Alison, Simone Carradori, Claudiu T Supuran, Licia Rivoltini, Chiara Castelli, Vincenzo Mazzaferro
Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity...
2018: Oncoimmunology
Jakob Nikolas Kather, Anna Sophie Berghoff, Dyke Ferber, Meggy Suarez-Carmona, Constantino Carlos Reyes-Aldasoro, Nektarios A Valous, Rodrigo Rojas-Moraleda, Dirk Jäger, Niels Halama
Cancer immunotherapy has fundamentally changed the landscape of oncology in recent years and significant resources are invested into immunotherapy research. It is in the interests of researchers and clinicians to identify promising and less promising trends in this field in order to rationally allocate resources. This requires a quantitative large-scale analysis of cancer immunotherapy related databases. We developed a novel tool for text mining, statistical analysis and data visualization of scientific literature data...
2018: Oncoimmunology
Baptiste Lamarthée, Frédéric de Vassoigne, Florent Malard, Nicolas Stocker, Inès Boussen, Clémence Médiavilla, Ruoping Tang, Fanny Fava, Laurent Garderet, Zora Marjanovic, Eolia Brissot, Mohamad Mohty, Béatrice Gaugler
Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity...
2018: Oncoimmunology
Tsuyoshi Hamada, Thing Rinda Soong, Yohei Masugi, Keisuke Kosumi, Jonathan A Nowak, Annacarolina da Silva, Xinmeng Jasmine Mu, Tyler S Twombly, Hideo Koh, Juhong Yang, Mingyang Song, Li Liu, Mancang Gu, Yan Shi, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Sachet A Shukla, Catherine J Wu, Levi A Garraway, Xuehong Zhang, Kana Wu, Jeffrey A Meyerhardt, Andrew T Chan, Jonathan N Glickman, Scott J Rodig, Gordon J Freeman, Charles S Fuchs, Reiko Nishihara, Marios Giannakis, Shuji Ogino
Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 ( PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274 low /TILabsent ; TIME 2, CD274 high /TILpresent ; TIME 3, CD274 low /TILpresent ; and TIME 4, CD274 high /TILabsent )...
2018: Oncoimmunology
Kirtesh R Patel, Anthony Martinez, John M Stahl, Suzanna J Logan, Adam J Perricone, Matthew J Ferris, Zachary S Buchwald, Mudit Chowdhary, Keith A Delman, David K Monson, Shervin V Oskouei, Nicholas B Reimer, Kenneth Cardona, Mark A Edgar, Karen D Godette
Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling)...
2018: Oncoimmunology
Guohui Qin, Jingyao Lian, Lan Huang, Qitai Zhao, Shasha Liu, Zhen Zhang, Xinfeng Chen, Dongli Yue, Lifeng Li, Feng Li, Lidong Wang, Viktor Umansky, Bin Zhang, Shengli Yang, Yi Zhang
Purpose : Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured...
2018: Oncoimmunology
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