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Maria E Rodriguez-Ruiz, Inmaculada Rodriguez, Lina Mayorga, Tania Labiano, Benigno Barbes, Inaki Etxeberria, Mariano Ponz-Sarvise, Arantza Azpilikueta, Elixabet Bolaños, Miguel F Sanmamed, Pedro Berraondo, Felipe A Calvo, Mary Helen Barcellos-Hoff, Jose Luis Perez-Gracia, Ignacio Melero
Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF-beta expression or activation increases in irradiated tissues, we tested whether TGF-beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination...
January 25, 2019: Molecular Cancer Therapeutics
Tadanobu Nagaya, Jay Friedman, Yasuhiro Maruoka, Fusa Ogata, Shuhei Okuyama, Paul E Clavijo, Peter L Choyke, Clint Allen, Hisataka Kobayashi
Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death, but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced de novo tumor antigen-specific T-cell responses absent at baseline...
January 25, 2019: Cancer Immunology Research
Eric Freund, Kim Rouven Liedtke, Julia van der Linde, Hans-Robert Metelmann, Claus-Dieter Heidecke, Lars-Ivo Partecke, Sander Bekeschus
Metastatic colorectal cancer is the fourth most common cause of cancer death. Current options in palliation such as hyperthermic intraperitoneal chemotherapy (HIPEC) present severe side effects. Recent research efforts suggested the therapeutic use of oxidant-enriched liquid using cold physical plasma. To investigate a clinically accepted treatment regimen, we assessed the antitumor capacity of plasma-treated saline solution. In response to such liquid, CT26 murine colon cancer cells were readily oxidized and showed cell growth with subsequent apoptosis, cell cycle arrest, and upregulation of immunogenic cell death (ICD) markers in vitro...
January 24, 2019: Scientific Reports
Jonathan A Hensel, Vinayak Khattar, Reading Ashton, Selvarangan Ponnazhagan
Carcinoembryonic antigen (CEA) is a human glycoprotein involved in cellular adhesion and expressed during human fetal development. Although expression of CEA largely ceases prior to birth, several human epithelial cancers, including colorectal, gastric, squamous esophageal, and breast carcinomas have been known to overexpress CEA, suggesting its potential as an immunotherapeutic target. Using a transgenic mouse model constitutively expressing human CEA in a spatiotemporal manner as a self-protein and a syngeneic mouse colon cancer cell line, MC38-CEA, overexpressing CEA, we tested the potential of a novel genetic immunotherapy approach against CEA-expressing tumors, using recombinant adeno-associated virus vector encoding CEA (rAAV-CEA) and appropriately timed immune adjuvant application...
March 29, 2019: Molecular Therapy Oncolytics
Kerstin Kapp, Barbara Volz, Michael A Curran, Detlef Oswald, Burghardt Wittig, Manuel Schmidt
BACKGROUND: Toll-like receptor 9 agonists are potent activators of the immune system. Their clinical potential in immunotherapy against metastatic cancers is being evaluated across a number of clinical trials. TLR9 agonists are DNA-based molecules that contain several non-methylated CG-motifs for TLR9 recognition. Chemical modifications of DNA backbones are usually employed to prevent degradation by nucleases. These, however, can promote undesirable off-target effects and therapeutic restrictions...
January 8, 2019: Journal for Immunotherapy of Cancer
Lenneke A M Cornelissen, Athanasios Blanas, Joost C van der Horst, Laura Kruijssen, Anouk Zaal, Tom O'Toole, Lieke Wiercx, Yvette van Kooyk, Sandra J van Vliet
Sialylated glycan structures are known for their immunomodulatory capacities and their contribution to tumor immune evasion. However, the role of aberrant sialylation in colorectal cancer and the consequences of complete tumor desialylation on anti-tumor immunity remain unstudied. Here, we report that CIRSPR/Cas9-mediated knock out of the CMAS gene, encoding a key enzyme in the sialylation pathway, in the mouse colorectal cancer MC38 cell line completely abrogated cell surface expression of sialic acids (MC38-Sianull ) and, unexpectedly, significantly increased in vivo tumor growth compared to the control MC38-MOCK cells...
December 22, 2018: International Journal of Cancer. Journal International du Cancer
Xiu-Man Zhou, Wan-Qiong Li, Ya-Hong Wu, Lu Han, Xin-Guang Cao, Xuan-Ming Yang, Hong-Fei Wang, Wen-Shan Zhao, Wen-Jie Zhai, Yuan-Ming Qi, Yan-Feng Gao
TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro , the tumor growth in mice was considerably inhibited...
2018: Frontiers in Immunology
Wei-Wei Pan, Toshiro Moroishi, Ja Hyun Koo, Kun-Liang Guan
The Hippo pathway controls organ size and tissue homeostasis, and its dysregulation often contributes to tumorigenesis. Extensive studies have shown that the Hippo pathway inhibits cell proliferation, and survival in a cell-autonomous manner. We examined the function of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in cancer cells. As expected, loss of LATS1/2 promotes cancer cell growth in most cell lines. Surprisingly, however, LATS1/2 deletion inhibits the growth of murine MC38 colon cancer cells, especially under detachment conditions...
December 10, 2018: Oncogene
Wenjun Wang, Zhida Liu, Xiaoxiao Zhou, Zhenqian Guo, Jing Zhang, Ping Zhu, Sheng Yao, Mingzhao Zhu
Recently, tumor neoantigens have been attractive for development of personal therapeutic vaccines. However, how to instantly deliver multiple neoantigens for efficient anti-tumor immunity is still challenging. Here, we established a SpyCatcher-modified ferritin nanoparticle platform, which permits convenient and stable covalent conjugation with tumor specific antigens containing SpyTag in a click-link manner. These ferritin nanoparticles are rapidly drained to lymph nodes and target dendritic cells, especially CD8α+ population, upon subcutaneous immunization...
December 8, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
Gang Shi, Qianmei Yang, Yujing Zhang, Qingyuan Jiang, Yi Lin, Shenshen Yang, Huiling Wang, Lin Cheng, Xin Zhang, Yimin Li, Qingnan Wang, Yi Liu, Qin Wang, Hantao Zhang, Xiaolan Su, Lei Dai, Lei Liu, Shuang Zhang, Jia Li, Zhi Li, Yang Yang, Dechao Yu, Yuquan Wei, Hongxin Deng
Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer...
November 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
A Blanas, L A M Cornelissen, M Kotsias, J C van der Horst, H J van de Vrugt, H Kalay, D I R Spencer, R P Kozak, S J van Vliet
Aberrant fucosylation in cancer cells is considered as a signature of malignant cell transformation and it is associated with tumor progression, metastasis and resistance to chemotherapy. Specifically, in colorectal cancer cells, increased levels of the fucosylated Lewisx antigen are attributed to the deregulated expression of pertinent fucosyltransferases, like fucosyltransferase 4 (FUT4) and fucosyltransferase 9 (FUT9). However, the lack of experimental models closely mimicking cancer-specific regulation of fucosyltransferase gene expression has, so far, limited our knowledge regarding the substrate specificity of these enzymes and the impact of Lewisx synthesis on the glycome of colorectal cancer cells...
November 22, 2018: Glycobiology
Keaton I Jones, Jiske Tiersma, Arseniy E Yuzhalin, Alex N Gordon-Weeks, Jon Buzzelli, Jae Hong Im, Ruth J Muschel
Emerging evidence suggests a role for radiation in eliciting anti-tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony-stimulating factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour-associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype...
November 15, 2018: EMBO Molecular Medicine
Juhyun Oh, Angela Magnuson, Christophe Benoist, Mikael J Pittet, Ralph Weissleder
Cancer incidence increases with age, but paradoxically, cancers have been found to grow more quickly in young mice compared with aged ones. The cause of differential tumor growth has been debated and, over time, attributed to faster tumor cell proliferation, decreased tumor cell apoptosis, and/or increased angiogenesis in young animals. Despite major advances in our understanding of tumor immunity over the past 2 decades, little attention has been paid to comparing immune cell populations in young and aged mice...
November 2, 2018: JCI Insight
Chloé Grasselly, Morgane Denis, Aurore Bourguignon, Nolan Talhi, Doriane Mathe, Anne Tourette, Laurent Serre, Lars Petter Jordheim, Eva Laure Matera, Charles Dumontet
In spite of impressive response rates in multiple cancer types, immune checkpoint inhibitors (ICIs) are active in only a minority of patients. Alternative strategies currently aim to combine immunotherapies with conventional agents such as cytotoxic chemotherapies. Here, we performed a study of PD-1 or PDL-1 blockade in combination with reference chemotherapies in four fully immunocompetent mouse models of cancer. We analyzed both the in vivo antitumor response, and the tumor immune infiltrate 4 days after the first treatment...
2018: Frontiers in Immunology
Long Wang, Yuxi Zhou, Jiemin Yin, Yu Gan, Xin Wang, Daxiang Wen, Angus W Thomson, Xiaoming Hu, Liqun Yang, R Anne Stetler, Peiying Li, Weifeng Yu
Background and Purpose- Adoptive transfer of regulatory T cells (Tregs) protect against stroke; however, Treg-based therapy raises concerns in stroke patients with cancer because of the immunosuppressive function of Tregs. The purpose of this study was to investigate the role of Tregs in cerebral ischemic brain injury with concomitant cancer. Methods- To establish a cancer phenotype, MC38 colon cancer or B16 melanoma cells (5×105 /mice) were injected subcutaneously into C57BL/6J mice 2 to 3 weeks before distal middle cerebral artery occlusion surgery...
November 2018: Stroke; a Journal of Cerebral Circulation
Shu-Han Yu, Janielle P Maynard, Ajay M Vaghasia, Angelo M De Marzo, Charles G Drake, Karen S Sfanos
BACKGROUND: Interleukin-6 (IL-6) is a mediator of inflammation that can facilitate prostate cancer progression. We previously demonstrated that IL-6 is present in the prostate tumor microenvironment and is restricted almost exclusively to the stromal compartment. The present study examined the influence of paracrine IL-6 signaling on prostate tumor growth using allograft models of mouse prostate cancer (TRAMP-C2), colon cancer (MC38), and melanoma (B16) cell lines in wildtype (WT) and IL-6 knockout (IL-6-/- ) mice...
October 21, 2018: Prostate
Benjamin M Larimer, Emily G Bloch, Sarah Nesti, Emily E Austin, Eric Wehrenberg-Klee, Genevieve Boland, Umar Mahmood
PURPOSE: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy. EXPERIMENTAL DESIGN: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Meinolf Thiemann, David M Richards, Karl Heinonen, Michael Kluge, Viola Marschall, Christian Merz, Mauricio Redondo Müller, Tim Schnyder, Julian P Sefrin, Jaromir Sykora, Harald Fricke, Christian Gieffers, Oliver Hill
Tumor necrosis factor receptor superfamily member 7 (TNFRSF7, CD27), expressed primarily by T cells, and its ligand CD27L (TNFSF7, CD70) provide co-stimulatory signals that boost T cell activation, differentiation, and survival. Agonistic stimulation of CD27 is therefore a promising therapeutic concept in immuno-oncology intended to boost and sustain T cell driven anti-tumor responses. Endogenous TNFSF/TNFRSF-based signal transmission is a structurally well-defined event that takes place during cell-to-cell-based contacts...
2018: Frontiers in Oncology
Alfonso R Sanchez-Paulete, Alvaro Teijeira, Jose I Quetglas, Maria E Rodriguez-Ruiz, Alvaro Sanchez-Arraez, Sara Labiano, Inaki Etxeberria, Arantza Azpilikueta, Elixabet Bolaños, Maria Cristina Ballesteros-Briones, Noelia Casares, Sergio A Quezada, Pedro Berraondo, David Sancho, Cristian Smerdou, Ignacio Melero
Multiple lines of evidence indicate a critical role for antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1 respectively constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to tumor cells in culture and when engrafted as subcutaneous mouse tumor models...
October 8, 2018: Cancer Research
Christian Merz, Jaromir Sykora, Viola Marschall, David M Richards, Karl Heinonen, Mauricio Redondo Müller, Meinolf Thiemann, Tim Schnyder, Harald Fricke, Oliver Hill, Christian Gieffers
CD40 ligand (TNFSF5/CD154/CD40L), a member of the tumor necrosis factor (TNF) superfamily is a key regulator of the immune system. The cognate receptor CD40 (TNFRSF5) is expressed broadly on antigen-presenting cells and many tumor types, and has emerged as an attractive target for immunologic cancer treatment. Most of the CD40 targeting drugs in clinical development are antibodies which display some disadvantages: their activity typically depends on Fcγ receptor-mediated crosslinking, and depletion of CD40-expressing immune cells by antibody-dependent cellular cytotoxicity compromises an efficient antitumor response...
November 2018: Journal of Immunotherapy
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