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Zheng Liu, Yu Zhu, Le Xu, Junyu Zhang, Huyang Xie, Hangcheng Fu, Quan Zhou, Yuan Chang, Bo Dai, Jiejie Xu
Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms...
2018: Oncoimmunology
Roy Xiao, Clint T Allen, Linda Tran, Priya Patel, So-Jin Park, Zhong Chen, Carter Van Waes, Nicole C Schmitt
Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNFα...
2018: Oncoimmunology
Marton Keszei, Joanna S Kritikou, Deborah Sandfort, Minghui He, Mariana M S Oliveira, Hannah Wurzer, Raoul V Kuiper, Lisa S Westerberg
The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton in hematopoietic cells and mutated in two severe immunodeficiency diseases with high incidence of cancer. Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in WASp and most frequently associated with lymphoreticular tumors of poor prognosis. X-linked neuropenia (XLN) is caused by gain-of-function mutations in WASp and associated with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To understand the role of WASp in tumorigenesis, we bred WASp+ , WASp- , and WASp-XLN mice onto tumor susceptible p53+/- background and sub-lethally irradiated them to enhance tumor development...
2018: Oncoimmunology
Bogang Wu, Xiujie Sun, Harshita B Gupta, Bin Yuan, Jingwei Li, Fei Ge, Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Deyi Zhang, Jing Yang, Yanfen Hu, Tyler J Curiel, Rong Li
Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes...
2018: Oncoimmunology
Franziska Eckert, Philipp Schaedle, Daniel Zips, Barbara Schmid-Horch, Hans-Georg Rammensee, Cihan Gani, Cécile Gouttefangeas
Combination of radiotherapy with immunotherapy has become an attractive concept for the treatment of cancer. The objective of this study was to assess the effect of curative, normofractionated radiotherapy on peripheral immune lymphocytes in prostate cancer patients, in order to propose a rationale for scheduling of normofractionated radiotherapy with T-cell based immunotherapy. In a prospective study ( NCT01376674), eighteen patients with localized prostate cancer were treated with radiotherapy with or without hormonal therapy...
2018: Oncoimmunology
Giulia Mesiano, Giovanni Grignani, Erika Fiorino, Valeria Leuci, Ramona Rotolo, Lorenzo D'Ambrosio, Chiara Salfi, Loretta Gammaitoni, Lidia Giraudo, Alberto Pisacane, Sara Butera, Ymera Pignochino, Marco Basiricó, Federica Capozzi, Anna Sapino, Massimo Aglietta, Dario Sangiolo
Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunotherapy activity of cytokine induced killer cells (CIK) against autologous sCSC that survived CHT and mTT. The experimental platform included two aggressive bone and soft tissue sarcoma models: osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS)...
2018: Oncoimmunology
Sadia Zafar, Suvi Sorsa, Mikko Siurala, Otto Hemminki, Riikka Havunen, Victor Cervera-Carrascon, João Manuel Santos, Hongjie Wang, Andre Lieber, Tanja De Gruijl, Anna Kanerva, Akseli Hemminki
Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach in cancer immunotherapy. One of the major obstacles in cancer immunotherapy in general is the immunosuppressive tumor microenvironment, which hampers the maturation and activation of DCs. Therefore, human clinical outcomes with DC therapy alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing human CD40L, to modulate the tumor microenvironment with subsequently improved function of DCs...
2018: Oncoimmunology
Alexandra Thomas, Eric D Routh, Ashok Pullikuth, Guangxu Jin, Jing Su, Jeff W Chou, Katherine A Hoadley, Cristin Print, Nick Knowlton, Michael A Black, Sandra Demaria, Ena Wang, Davide Bedognetti, Wendell D Jones, Gaurav A Mehta, Michael L Gatza, Charles M Perou, David B Page, Pierre Triozzi, Lance D Miller
Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively)...
2018: Oncoimmunology
Eliza Kwiatkowska-Borowczyk, Patrycja Czerwińska, Jacek Mackiewicz, Katarzyna Gryska, Urszula Kazimierczak, Katarzyna Tomela, Anna Przybyła, Anna Karolina Kozłowska, Łukasz Galus, Łukasz Kwinta, Ewelina Dondajewska, Agnieszka Gąbka-Buszek, Monika Żakowska, Andrzej Mackiewicz
Allogeneic whole cell gene modified therapeutic melanoma vaccine (AGI-101H) comprising of two melanoma cell lines transduced with cDNA encoding fusion protein composed of IL-6 linked with the soluble IL-6 receptor (sIL-6R), referred to as H6 was developed. H6 served as a molecular adjuvant, however, it has altered vaccine cells phenotype towards melanoma stem cells (MSC)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). AGI-101H was applied in advanced melanoma patients with non-resected and resected disease...
2018: Oncoimmunology
Jeremiah L Oyer, Sarah B Gitto, Deborah A Altomare, Alicja J Copik
Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model...
2018: Oncoimmunology
Jibran Ahmed, Arun Kumar, Kaushal Parikh, Asad Anwar, Bettina M Knoll, Carmelo Puccio, Hoo Chun, Michael Fanucchi, Seah H Lim
We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger ( p  = 0.0008) and less likely to receive nivolumab ( p  = 0.08) or had neutrophil:lymphocyte ratio < 5 ( p  = 0.08). They had a lower response rate (RR) (29...
2018: Oncoimmunology
Kara W Moyes, Amira Davis, Virginia Hoglund, Kristen Haberthur, Nicole Ap Lieberman, Shannon A Kreuser, Gail H Deutsch, Stephanie Franco, Darren Locke, Michael O Carleton, Debra G Gilbertson, Randi Simmons, Conrad Winter, John Silber, Luis F Gonzalez-Cuyar, Richard G Ellenbogen, Courtney A Crane
Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens...
2018: Oncoimmunology
Dedong Cao, Huilin Xu, Ximing Xu, Tao Guo, Wei Ge
Objective : Nivolumab has been used for treating non-small cell lung cancer (NSCLC) worldwide. Whether neutrophil-lymphocyte ratio (NLR) can predict the prognosis of NSCLC treated with Nivolumab is still under debate. This meta-analysis was to assess the significance of NLR as a predictive factor in NSCLC patients receiving Nivolumab. Methods : Databases including PubMed, Embase, and the Cochrane library were searched to identify eligible studies evaluating the role of NLR in predicting prognosis of NSCLC treated with Nivolumab until March 2018 without language restrictions...
2018: Oncoimmunology
Yingxin Yu, Bart Blokhuis, Yvonne Derks, Sangeeta Kumari, Johan Garssen, Frank Redegeld
Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. Mast cells (MC), one of earliest recruited immune cells, accumulate in CRC tissues and their density is correlated with cancer progression. However, the exact contribution of MC in CRC and their interaction with colon cancer cells is poorly understood. Here, we investigated the impact of primary human MC and their mediators on colon cancer growth using 2D and 3D coculture models...
2018: Oncoimmunology
Shuai Wang, Qian Zhang, Qinlan Wang, Qicong Shen, Xiang Chen, Zhenyang Li, Ye Zhou, Jin Hou, Bowen Xu, Nan Li, Xuetao Cao
The formation of paraspeckle, a stress-induced nuclear body, increases in response to viral infection or proinflammatory stimuli. Paraspeckle consists of lncRNA (nuclear paraspeckle assembly transcript 1, NEAT1) and protein components including NONO, SFPQ, PSPC1, etc., which are shown to be involved in viral infection and cancer. Both NEAT1 and NONO expression increase in human hepatocellular carcinoma (HCC) samples according to TCGA data. However, the role of paraspeckle in HCC progression needs further identification...
2018: Oncoimmunology
Samantha Burugu, Dongxia Gao, Samuel Leung, Stephen K Chia, Torsten O Nielsen
Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy...
2018: Oncoimmunology
Louise Soo Yee Tan, Benjamin Wong, Nagaraja Rao Gangodu, Andrea Zhe Ern Lee, Anthony Kian Fong Liou, Kwok Seng Loh, Hao Li, Ming Yann Lim, Andres M Salazar, Chwee Ming Lim
Cetuximab immunotherapy targeting the epidermal growth factor receptor (EGFR) has been used to treat nasopharyngeal cancer (NPC) with some success. Therefore, combining an immune adjuvant to boost the immune microenvironment may improve its clinical efficacy. Herein, we investigate the immune-stimulatory effects of Poly-ICLC (a TLR3 agonist) in enhancing cetuximab-based immunotherapy and correlate these responses with FcɣRIIIa (V158F) or TLR3 single nucleotide polymorphisms (SNPs- L412F and C829T) expressed on immune effector cells...
2018: Oncoimmunology
Neal Bhutiani, Qingsheng Li, Charles D Anderson, Heather C Gallagher, Magdia De Jesus, Rajbir Singh, Venkatkrishna R Jala, Mostafa Fraig, Tao Gu, Nejat K Egilmez
Oral IL-10 suppressed tumor growth in the APCmin/+ mouse/ Bacteroides fragilis colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.e. IL-10 diminished Th17 cell prevalence whereas IL-12 induced IFNγ and enhanced CD8 + T-cell activity. Loss-of-function studies demonstrated that IL-12-driven CD8 + T-cell expansion was only partially responsible for the synergy, and that both the detrimental and the beneficial activities of IL-12 required IFNγ...
2018: Oncoimmunology
Ting Wu, Chaohui Wang, Weihong Wang, Yuhang Hui, Rongxin Zhang, Liang Qiao, Yun Dai
Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment and has been recognized as a contributing factor for inflammation-related cancers. We previously showed that embelin has potent anti-inflammatory and anti-tumor effects in a colitis-associated cancer (CAC) model. Here, by using this model, we assessed the effect of embelin on the accumulation and suppressive function of MDSCs. We have demonstrated that embelin substantially reduced accumulation of MDSCs in the peripheral lymphoid organ and tumor tissue of CAC-bearing mice...
2018: Oncoimmunology
Benjamin A Kansy, Gulidanna Shayan, Hyun-Bae Jie, Sandra P Gibson, Yu L Lei, Sven Brandau, Stephan Lang, Nicole C Schmitt, Fei Ding, Yan Lin, Robert L Ferris
The role of T cell receptor (TCR) signaling for adaptive immune responses is essential. The ability to respond to a broad spectrum of tumor antigens requires an adaptive selection of various TCR. So far, little is known about the role of TCR richness and clonality in the cellular immune response to head and neck cancer (HNC), though the Endothelial Growth Factor Receptor (EGFR)-specific CD8+ T cell response can be enhanced by cetuximab therapy. Therefore, we investigated differences in TCR sequences between human papillomavirus (HPV)+ and HPV- HNC patients, as well as differences in TCR sequence characteristics between T cells of peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL)...
2018: Oncoimmunology
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