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Cancer Immunology Research

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February 16, 2018: Cancer Immunology Research
Dylan J Martini, Lana Hamieh, Rana R McKay, Lauren C Harshman, Raphael Brandao, Craig K Norton, John A Steinharter, Katherine M Krajewski, Xin Gao, Fabio A Schutz, Bradley McGregor, Dominick Bosse, Aly-Khan Lalani, Guillermo de Velasco, M Dror Michaelson, David F McDermott, Toni K Choueiri
The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAEs) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary end-point was time to progression from the date of treatment cessation (TTP)...
February 1, 2018: Cancer Immunology Research
Agnieszka Witalisz-Siepracka, Dagmar Gotthardt, Michaela Prchal-Murphy, Zrinka Didara, Ingeborg Menzl, Daniela Prinz, Leo Edlinger, Eva Maria Putz, Veronika Sexl
Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses...
January 31, 2018: Cancer Immunology Research
Sobha R Bodduluri, Steven Mathis, Paramahamsa Maturu, Elangovan Krishnan, Shuchismita R Satpathy, Paula M Chilton, Thomas Mitchell, Sergio A Lira, Massimo Locati, Alberto Mantovani, Venkatakrishna R Jala, Bodduluri Haribabu
The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the adenomatous polyposis coli gene (ApcMin/+) displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2-/-ApcMin/+ tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell-deficient ACKR2-/-SA-/-ApcMin/+ mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth...
January 30, 2018: Cancer Immunology Research
Min Hwan Kim, Chang Gon Kim, Sang-Kyum Kim, Sang Joon Shin, Eun Ah Choe, Su-Hyung Park, Eui-Cheol Shin, Joon Kim
Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8+ T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition...
January 30, 2018: Cancer Immunology Research
Aaron Lisberg, D Andrew Tucker, Jonathan W Goldman, Brian Wolf, James Carroll, Ariana Hardy, Karolyn Morris, Paulina Linares, Carlos Adame, Marshall L Spiegel, Courtney Wells, Jordan McKenzie, Blanca Ledezma, Melody Mendenhall, Phillip Abarca, Krikor Bornazyan, Jaime Hunt, Nima Moghadam, Natalie Chong, Danielle Nameth, Caitlin Marx, John Madrigal, Sitaram Vangala, Narek Shaverdian, David A Elashoff, Edward B Garon
We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to CTCAE v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated...
January 30, 2018: Cancer Immunology Research
Benjamin Solomon, Richard J Young, Mathias Bressel, Damien Urban, Shona Hendry, Alesha Thai, Christopher Angel, Afaf Haddad, Marcin Kowanetz, Tsien Fua, June Corry, Stephen Fox, Danny Rischin
Human papilloma virus positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represent a distinct subgroup of head and neck cancers associated with clinical outcomes that are not accurately categorized by existing TNM-based staging methods. Given the significant impact of immune parameters, such as tumor infiltrating lymphocytes (TILs) in many cancers, we sought to determine if immunophenotyping tumors can improve categorization of HPV+ OPSCCs for prognostic purposes. In a cohort of 190 patients with HPV+ OPSCC, we quantified and determined the localization of CD8+ TILs, as well as PD-L1-expressing tumor cells (TCs) and immune cells (ICs)...
January 29, 2018: Cancer Immunology Research
Sho Miyamoto, Vitaly Kochin, Takayuki Kanaseki, Ayumi Hongo, Serina Tokita, Yasuhiro Kikuchi, Akari Takaya, Yoshihiko Hirohashi, Tomohide Tsukahara, Takeshi Terui, Kunihiko Ishitani, Fumitake Hata, Ichiro Takemasa, Akihiro Miyazaki, Hiroyoshi Hiratsuka, Noriyuki Sato, Toshihiko Torigoe
Colorectal cancer consists of a small number of cancer stem cells (CSCs) and many non-CSCs. Although rare in number, CSCs are a target for cancer therapy, because they survive conventional chemo- and radiotherapies and perpetuate tumor formation in vivo. In this study, we conducted an HLA ligandome analysis to survey HLA-A24 peptides displayed by CSCs and non-CSCs of colorectal cancer. The analysis identified an antigen, ASB4, which was processed and presented by a CSC subset but not by non-CSCs. The ASB4 gene was expressed in CSCs of colorectal cancer, but not in cells that had differentiated into non-CSCs...
January 25, 2018: Cancer Immunology Research
Keisuke Ogura, Marimo Sato-Matsushita, Seiji Yamamoto, Takashi Hori, Masakiyo Sasahara, Yoichiro Iwakura, Ikuo Saiki, Hideaki Tahara, Yoshihiro Hayakawa
Although NK cells are recognized as direct antitumor effectors, the ability of NK cells to control cancer-associated inflammation, which facilitates tumor progression, remains unknown. In this study, we demonstrate that NK cells control tumor-promoting inflammation through functional modification of neutrophils. NK cells control the tumor-promoting function of neutrophils through an IFNgamma-dependent mechanism. Tumor progression in an NK cell-depleted host is diminished when the IL17A-neutrophil axis is absent...
January 23, 2018: Cancer Immunology Research
Rafael Samaniego, Alejandra Gutierrez-Gonzalez, Alba Gutierrez-Seijo, Sandra Sanchez-Gregorio, Jorge García-Gimenez, Enrique Mercader, Ivan Marquez-Rodas, Jose Antonio Aviles, Miguel Relloso, Paloma Sanchez-Mateos
The chemokine axis CCR6/CCL20 is involved in cancer progression in a variety of tumors. Here we show that CCR6 is expressed by melanoma cells. The CCR6 ligand, CCL20, induces migration and proliferation in vitro, and enhances tumor growth and metastasis in vivo. Confocal analysis of melanoma tissues showed that CCR6 is expressed by tumor cells, whereas CCL20 is preferentially expressed by non-tumoral cells in the stroma of certain tumors. Stromal CCL20, but not tumoral CCR6, predicted poor survival in a cohort of 40 primary melanoma patients...
January 23, 2018: Cancer Immunology Research
Yi-Hsin Lin, Ming-Chieh Yang, Ssu-Hsueh Tseng, Rosie Jiang, Andrew Yang, Emily Farmer, Shiwen Peng, Talia Henkle, Yung-Nien Chang, Chien-Fu Hung, T-C Wu
Human papillomavirus type 16 (HPV16) is the etiologic factor for cervical cancer and a subset of oropharyngeal cancers. Although several prophylactic HPV vaccines are available, no effective therapeutic strategies to control active HPV diseases exist. Tumor implantation models are traditionally used to study HPV-associated buccal tumors. However, they fail to address precancerous phases of disease progression and display tumor microenvironments distinct from those observed in patients. Previously, K14-E6/E7 transgenic mouse models have been used to generate spontaneous tumors...
January 23, 2018: Cancer Immunology Research
Neidy Varela Rodrigues, Daniel V Correia, Sofia Mensurado, Sandrina Nobrega-Pereira, Ana deBarros, Fernanda Kyle-Cezar, Andrew Tutt, Adrian C Hayday, Haakan Norell, Bruno Silva-Santos, Sergio Dias
Vgamma9Vdelta2 T cells, the main subset of gamma delta T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFNgamma production. These functions are triggered upon TCR-dependent activation by non-peptidic prenyl pyrophosphates ("phosphoantigens") that are selective agonists of Vgamma9Vdelta2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown inter-individual variation in Vgamma9Vdelta2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated Vgamma9Vdelta2 T-cell activation and function...
January 22, 2018: Cancer Immunology Research
Sumiyuki Nishida, Takeshi Ishikawa, Shinichi Egawa, Shigeo Koido, Hiroaki Yanagimoto, Jun Ishii, Yoshihide Kanno, Satoshi Kokura, Hiroaki Yasuda, Mari Saito Oba, Maho Sato, Soyoko Morimoto, Fumihiro Fujiki, Hidetoshi Eguchi, Hiroaki Nagano, Atsushi Kumanogoh, Michiaki Unno, Masanori Kon, Hideaki Shimada, Kei Ito, Sadam Homma, Yoshihiro Oka, Satoshi Morita, Haruo Sugiyama
We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it to gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01- or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTLs)...
January 22, 2018: Cancer Immunology Research
Charlotte E Ariyan, Mary Sue Brady, Robert H Siegelbaum, Jian Hu, Danielle M Bello, Jamie Green, Charles Fisher, Robert A Lefkowitz, Katherine S Panageas, Melissa Pulitzer, Marissa Vignali, Ryan Emerson, Christopher Tipton, Harlan Robins, Taha Merghoub, Jianda Yuan, Achim Jungbluth, Jorge Blando, Padmanee Sharma, Alexander Y Rudensky, Jedd D Wolchok, James P Allison
Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a non-inflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio...
January 16, 2018: Cancer Immunology Research
Andrew J Rech, David Balli, Alejandro Mantero, Hemant Ishwaran, Katherine L Nathanson, Ben Z Stanger, Robert H Vonderheide
The immune system exerts antitumor activity via T cell-dependent recognition of tumor-specific antigens. Although the number of tumor neopeptides - peptides derived from somatic mutations - often correlates with immune activity and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, and only rare CDNs have been linked to tumor rejection. Thus, the rules of tumor antigen recognition remain incompletely understood. Here, we analyzed neopeptides, immune activity, and clinical outcome from 6,324 patients across 27 tumor types...
January 16, 2018: Cancer Immunology Research
Ismail M Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veerabhadran Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji, Jack A Roth
Expression of the multikinase inhibitor encoded by tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1...
January 16, 2018: Cancer Immunology Research
Tina Nuebling, Carla Emilia Schumacher, Martin Hofmann, Ilona Hagelstein, Benjamin Joachim Schmiedel, Stefanie Maurer, Birgit Federmann, Kathrin Rothfelder, Malte Roerden, Daniela Dorfel, Pascal Schneider, Gundram Jung, Helmut Rainer Salih
The TNF receptor family member OX40 promotes activation and proliferation of T cells, which fuels efforts to modulate this immune checkpoint to reinforce antitumor immunity. Besides T cells, NK cells are a second cytotoxic lymphocyte subset that contributes to antitumor immunity, particularly in leukemia. Accordingly, these cells are being clinically evaluated for cancer treatment through multiple approaches, such as adoptive transfer of ex vivo expanded polyclonal NK cells (pNKC). Here we analyzed whether and how OX40 and its ligand (OX40L) influence NK-cell function and anti-leukemia reactivity...
January 10, 2018: Cancer Immunology Research
Galit Eisenberg, Roni Engelstein, Anat Geiger-Maor, Emma Hajaj, Sharon Merims, Shoshana Frankenburg, Ronny Uzana, Abraham Rutenberg, Arthur Machlenkin, Gabi Frei, Tamar Peretz, Michal Lotem
SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an antiapoptotic effect on tumor-infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity...
January 5, 2018: Cancer Immunology Research
Zuzana Berrong, Mikayel Mkrtichyan, Shamim Ahmad, Mason Webb, Eslam Mohamed, Grigori Okoev, Adelaida Matevosyan, Rajeev Shrimali, Rasha Abu Eid, Scott Hammond, John E Janik, Samir N Khleif
Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO- TC-1 tumor model...
January 5, 2018: Cancer Immunology Research
Gautam N Shenoy, Jenni L Loyall, Orla Maguire, Vandana Iyer, Raymond J Kelleher, Hans Minderman, Paul K Wallace, Kunle Odunsi, Sathy V Balu-Iyer, Richard B Bankert
Nano-sized membrane-encapsulated extracellular vesicles isolated from the ascites fluids of ovarian cancer patients are identified as exosomes based on their biophysical and compositional characteristics. We report here that T cells pulsed with these tumor-associated exosomes during TCR-dependent activation inhibit various activation endpoints including translocation of NFkB and NFAT into the nucleus, upregulation of CD69 and CD107a, production of cytokines and cell proliferation. Additionally, the activation of virus-specific CD8+ T cells that are stimulated with the cognate viral peptides presented in the context of class I MHC is also suppressed by the exosomes...
January 4, 2018: Cancer Immunology Research
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