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Erika Heninger, Timothy E G Krueger, Stephanie M Thiede, Jamie M Sperger, Brianna L Byers, Madison R Kircher, David Kosoff, Bing Yang, David F Jarrard, Douglas G McNeel, Joshua M Lang
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589...
October 17, 2016: Oncotarget
Ashton A Connor, Robert E Denroche, Gun Ho Jang, Lee Timms, Sangeetha N Kalimuthu, Iris Selander, Treasa McPherson, Gavin W Wilson, Michelle A Chan-Seng-Yue, Ivan Borozan, Vincent Ferretti, Robert C Grant, Ilinca M Lungu, Eithne Costello, William Greenhalf, Daniel Palmer, Paula Ghaneh, John P Neoptolemos, Markus Buchler, Gloria Petersen, Sarah Thayer, Michael A Hollingsworth, Alana Sherker, Daniel Durocher, Neesha Dhani, David Hedley, Stefano Serra, Aaron Pollett, Michael H A Roehrl, Prashant Bavi, John M S Bartlett, Sean Cleary, Julie M Wilson, Ludmil B Alexandrov, Malcolm Moore, Bradly G Wouters, John D McPherson, Faiyaz Notta, Lincoln D Stein, Steven Gallinger
Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium...
October 20, 2016: JAMA Oncology
Naoshi Nishida, Masatoshi Kudo
Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity...
October 21, 2016: Oncology
Peter Bailey, David K Chang, Marie-Andrée Forget, Francis A San Lucas, Hector A Alvarez, Cara Haymaker, Chandrani Chattopadhyay, Sun-Hee Kim, Suhendan Ekmekcioglu, Elizabeth A Grimm, Andrew V Biankin, Patrick Hwu, Anirban Maitra, Jason Roszik
Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases...
October 20, 2016: Scientific Reports
Paul Zolkind, Gavin P Dunn, Tianxiang Lin, Malachi Griffith, Obi L Griffith, Ravindra Uppaluri
The recent success of immunotherapies has demonstrated the potency of tumor-specific immune cells in mediating tumor rejection and generating durable tumor immunity. Our understanding of the scientific basis of these responses results from the confluence of a better comprehension of the cancer immunoediting process and the revolution in next generation sequencing of cancer genomes. Recent evidence suggests that T cell specificity for cancer cell expressed mutant proteins - termed neoantigens - is an important component of immune mediated tumor rejection...
October 14, 2016: Oral Oncology
Joshua J Meeks, Benedito A Carneiro, Sachin G Pai, Daniel T Oberlin, Alfred Rademaker, Kyle Fedorchak, Sohail Balasubramanian, Julia Elvin, Nike Beaubier, Francis J Giles
The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors")...
October 14, 2016: Oncotarget
Anna E Kersh, Maiko Sasaki, Lee A Cooper, Haydn T Kissick, Brian P Pollack
Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient's cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity...
2016: Frontiers in Pharmacology
Bart O Roep, Maria Jl Kracht, Menno van Lummel, Arnaud Zaldumbide
Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of the insulin-producing beta cells. Beta cell dysfunction caused by an inflammatory microenvironment is believed to trigger the peripheral activation of CD4 and CD8 autoreactive T cells. This review will compile post-transcriptional and post-translational modifications (PTM) involved in the generation of beta cell neoantigens and proposes a reconstruction of the sequence of events connecting environmental changes and autoimmunity...
October 7, 2016: Current Opinion in Immunology
Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Rie Sakakibara, Hironori Ninomiya, Sophia Subat, Hiroko Nagano, Kimie Nomura, Sakae Okumura, Tomoko Shibutani, Yuichi Ishikawa
OBJECTIVES: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients...
October 1, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Ji-Young Joo, Gil Sun Cha, Jin Chung, Ju-Youn Lee, Sung-Jo Kim, Jeomil Choi
BACKGROUND: Although periodontal pathogens show a strong association with the development of atherosclerosis, little is known about how a microorganism contributes to disease onset and progression. Oxidation of low-density lipoprotein (LDL) is a major risk factor of atherogenesis. The principal objective of our study was to evaluate the ability of peptide 19 (Pep19) of Porphyromonas gingivalis (P. gingivalis) heat shock protein (HSP) as a potent inducer of LDL oxidation, and as a secondary objective, to compare this ability with that of Pep19 from different bacteria...
October 7, 2016: Journal of Periodontology
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
Preeti Sharma, David M Kranz
Adoptive T-cell therapies have shown exceptional promise in the treatment of cancer, especially B-cell malignancies. Two distinct strategies have been used to redirect the activity of ex vivo engineered T cells. In one case, the well-known ability of the T-cell receptor (TCR) to recognize a specific peptide bound to a major histocompatibility complex molecule has been exploited by introducing a TCR against a cancer-associated peptide/human leukocyte antigen complex. In the other strategy, synthetic constructs called chimeric antigen receptors (CARs) that contain antibody variable domains (single-chain fragments variable) and signaling domains have been introduced into T cells...
2016: F1000Research
Jordan Kardos, Shengjie Chai, Lisle E Mose, Sara R Selitsky, Bhavani Krishnan, Ryoichi Saito, Michael D Iglesia, Matthew I Milowsky, Joel S Parker, William Y Kim, Benjamin G Vincent
We report the discovery of a claudin-low molecular subtype of high-grade bladder cancer that shares characteristics with the homonymous subtype of breast cancer. Claudin-low bladder tumors were enriched for multiple genetic features including increased rates of RB1, EP300, and NCOR1 mutations; increased frequency of EGFR amplification; decreased rates of FGFR3, ELF3, and KDM6A mutations; and decreased frequency of PPARG amplification. While claudin-low tumors showed the highest expression of immune gene signatures, they also demonstrated gene expression patterns consistent with those observed in active immunosuppression...
March 17, 2016: JCI Insight
David A Braun, Kelly P Burke, Eliezer M Van Allen
Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all, and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tanner M Johanns, Christopher A Miller, Ian G Dorward, Christina Tsien, Edward Chang, Arie Perry, Ravindra Uppaluri, Cole Ferguson, Robert E Schmidt, Sonika Dahiya, George Ansstas, Elaine R Mardis, Gavin P Dunn
We present the case of a patient with a left frontal glioblastoma with PNET features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with Pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors...
September 28, 2016: Cancer Discovery
J Galon, B A Fox, C B Bifulco, G Masucci, T Rau, G Botti, F M Marincola, G Ciliberto, F Pages, P A Ascierto, M Capone
The fifth "Melanoma Bridge Meeting" took place in Naples, December 1-5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient's clinical outcome...
2016: Journal of Translational Medicine
Rebecca A Evans, Mark S Diamond, Andrew J Rech, Timothy Chao, Max W Richardson, Jeffrey H Lin, David L Bajor, Katelyn T Byrne, Ben Z Stanger, James L Riley, Nune Markosyan, Rafael Winograd, Robert H Vonderheide
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy...
September 8, 2016: JCI Insight
David Gfeller, Michal Bassani-Sternberg, Julien Schmidt, Immanuel F Luescher
Tumor exome and RNA sequencing data provide a systematic and unbiased view on cancer-specific expression, over-expression, and mutations of genes, which can be mined for personalized cancer vaccines and other immunotherapies. Of key interest are tumor-specific mutations, because T cells recognizing neoepitopes have the potential to be highly tumoricidal. Here, we review recent developments and technical advances in identifying MHC class I and class II-restricted tumor antigens, especially neoantigen derived MHC ligands, including in silico predictions, immune-peptidome analysis by mass spectrometry, and MHC ligand validation by biochemical methods on T cells...
July 2016: Oncoimmunology
Roni Bareli, Cyrille J Cohen
Analysis of genomic data from patient tumors provides valuable information as to potential T-cell targets such as neoepitopes. We developed an approach to characterize, isolate and utilize neoantigens-specific T cells using MHC/peptide tetramers from fresh tumor digests and peripheral blood. This bears important implications for the implementation of T cell-based immunotherapy.
July 2016: Oncoimmunology
Maria Secrier, Xiaodun Li, Nadeera de Silva, Matthew D Eldridge, Gianmarco Contino, Jan Bornschein, Shona MacRae, Nicola Grehan, Maria O'Donovan, Ahmad Miremadi, Tsun-Po Yang, Lawrence Bower, Hamza Chettouh, Jason Crawte, Núria Galeano-Dalmau, Anna Grabowska, John Saunders, Tim Underwood, Nicola Waddell, Andrew P Barbour, Barbara Nutzinger, Achilleas Achilleos, Paul A W Edwards, Andy G Lynch, Simon Tavaré, Rebecca C Fitzgerald
Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro...
October 2016: Nature Genetics
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