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Epigenetics immune therapy cancer

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https://www.readbyqxmd.com/read/28644756/immunological-effects-of-hypomethylating-agents
#1
Katherine E Lindblad, Meghali Goswami, Christopher S Hourigan, Karolyn A Oetjen
Epigenetic changes resulting from aberrant methylation patterns are a recurrent observation in hematologic malignancies. Hypomethylating agents have a well-established role in the management of patients with high-risk myelodysplastic syndrome or acute myeloid leukemia. In addition to the direct effects of hypomethylating agents on cancer cells, there are several lines of evidence indicating a role for immune-mediated anti-tumor benefits from hypomethylating therapy. Areas Covered: We reviewed the clinical and basic science literature for the effects of hypomethylating agents, including the most commonly utilized therapeutics azacitidine and decitabine, on immune cell subsets...
June 23, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28628715/overcoming-the-resistance-of-pancreatic-cancer-to-immune-checkpoint-inhibitors
#2
REVIEW
Richard A Skelton, Ammar Javed, Lei Zheng, Jin He
Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors...
June 19, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28622390/inhibiting-dna-methylation-activates-cancer-testis-antigens-and-expression-of-the-antigen-processing-and-presentation-machinery-in-colon-and-ovarian-cancer-cells
#3
Cornelia Siebenkäs, Katherine B Chiappinelli, Angela A Guzzetta, Anup Sharma, Jana Jeschke, Rajita Vatapalli, Stephen B Baylin, Nita Ahuja
Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues...
2017: PloS One
https://www.readbyqxmd.com/read/28621264/dna-methylation-hydroxymethylation-in-melanoma
#4
REVIEW
Siqi Fu, Haijing Wu, Huiming Zhang, Christine G Lian, Qianjin Lu
Melanoma is a malignant tumor of melanocytes and is considered to be the most aggressive cancer among all skin diseases. The pathogenesis of melanoma has not been well documented, which may restrict the research and development of biomarkers and therapies. To date, several genetic and epigenetic factors have been identified as contributing to the development and progression of melanoma. Besides the findings on genetic susceptibilities, the recent progress in epigenetic studies has revealed that loss of the DNA hydroxymethylation mark, 5-hydroxymethylcytosine (5-hmC), along with high levels of DNA methylation at promoter regions of several tumor suppressor genes in melanoma, may serve as biomarkers for melanoma...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28609681/epigenetic-modulation-in-cancer-immunotherapy
#5
REVIEW
Stuart J Gallagher, Elena Shklovskaya, Peter Hersey
The success of immune checkpoint inhibitors in cancer immunotherapy has been widely heralded. However many cancer patients do not respond to immune checkpoint therapy and some relapse due to acquired tumor resistance. Epigenetic targeting may be beneficial in cancer immunotherapy by reversing immune avoidance and escape mechanisms employed by cancer cells, as well as by modulating immune cell differentiation and function. In this manuscript we review recent findings suggesting how epigenetics may be used to improve cancer immunotherapy...
June 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28595192/cancer-precision-medicine-why-more-is-more-and-dna-is-not-enough
#6
Moritz Schütte, Lesley A Ogilvie, Damian T Rieke, Bodo M H Lange, Marie-Laure Yaspo, Hans Lehrach
Every tumour is different. They arise in patients with different genomes, from cells with different epigenetic modifications, and by random processes affecting the genome and/or epigenome of a somatic cell, allowing it to escape the usual controls on its growth. Tumours and patients therefore often respond very differently to the drugs they receive. Cancer precision medicine aims to characterise the tumour (and often also the patient) to be able to predict, with high accuracy, its response to different treatments, with options ranging from the selective characterisation of a few genomic variants considered particularly important to predict the response of the tumour to specific drugs, to deep genome analysis of both tumour and patient, combined with deep transcriptome analysis of the tumour...
June 9, 2017: Public Health Genomics
https://www.readbyqxmd.com/read/28591094/non-clear-cell-renal-cell-carcinomas-biological-insights-and-therapeutic-challenges-and-opportunities
#7
Gabriel G Malouf, Richard W Joseph, Amishi Y Shah, Nizar M Tannir
The non-clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare-variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next-generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes...
May 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28576744/jak-stat-signaling-and-cancer-opportunities-benefits-and-side-effects-of-targeted-inhibition
#8
REVIEW
Bernd Groner, Viktoria von Manstein
The effects of Jak Stat signaling and the persistent activation of Stat3 and Stat5 on tumor cell survival, proliferation and invasion have made the Jak Stat pathway a favorite target for drug development and cancer therapy. This notion was strengthened when additional biological functions of Stat signaling in cancer and their roles in the regulation of cytokine dependent inflammation and immunity in the tumor microenvironment were discovered. Stats act not only as transcriptional inducers, but affect gene expression via epigenetic modifications, induce epithelial mesenchymal transition, generate a pro-tumorigenic microenvironment, promote cancer stem cell self-renewal and differentiation, and help to establish the pre-metastatic niche formation...
May 30, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28572863/epi-drugs-in-combination-with-immunotherapy-a-new-avenue-to-improve-anticancer-efficacy
#9
REVIEW
Roberta Mazzone, Clemens Zwergel, Antonello Mai, Sergio Valente
Immune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28561663/beyond-alkylating-agents-for-gliomas-quo-vadimus
#10
Vinay K Puduvalli, Rekha Chaudhary, Samuel G McClugage, James Markert
Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28561043/hsps-drive-dichotomous-t-cell-immune-responses-via-dna-methylome-remodelling-in-antigen-presenting-cells
#11
Lauren B Kinner-Bibeau, Abigail L Sedlacek, Michelle N Messmer, Simon C Watkins, Robert J Binder
Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28536458/epigenetic-priming-restores-the-hla-class-i-antigen-processing-machinery-expression-in-merkel-cell-carcinoma
#12
Cathrin Ritter, Kaiji Fan, Annette Paschen, Sine Reker Hardrup, Soldano Ferrone, Paul Nghiem, Selma Ugurel, David Schrama, Jürgen C Becker
Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host's immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2...
May 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28511092/epigenetics-and-immunotherapy-the-current-state-of-play
#13
REVIEW
Jennifer Dunn, Sudha Rao
Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant...
May 13, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28487862/naturally-occurring-canine-invasive-urinary-bladder-cancer-a-complementary-animal-model-to-improve-the-success-rate-in-human-clinical-trials-of-new-cancer-drugs
#14
REVIEW
Christopher M Fulkerson, Deepika Dhawan, Timothy L Ratliff, Noah M Hahn, Deborah W Knapp
Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models...
2017: International Journal of Genomics
https://www.readbyqxmd.com/read/28486273/zebularine-treatment-induces-mage-a11-expression-and-improves-ctl-cytotoxicity-using-a-novel-identified-hla-a2-restricted-mage-a11-peptide
#15
Jiandong Zhang, Meixiang Sang, Lina Gu, Fei Liu, Weijing Li, Danjing Yin, Yunyan Wu, Shina Liu, Weina Huang, Baoen Shan
Melanoma-associated antigen-A11 (MAGE-A11) is frequently expressed in breast cancer and is associated with poor prognosis. Therefore, MAGE-A11 is a potential immunotherapy target in breast cancer. MAGE-A11 expression, however, is downregulated in many patients, thus constraining the application of immunotherapy. The induction of MAGE-A11 expression is crucial for the recognition and killing of breast cancer cells by cytotoxic T lymphocytes (CTL). In this study, a series of HLA-A2-restricted candidate MAGE-A11 peptides were predicted, synthesized, and tested...
July 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28447025/metabolic-cooperation-and-competition-in-the-tumor-microenvironment-implications-for-therapy
#16
REVIEW
Seema Gupta, Amrita Roy, Bilikere S Dwarakanath
The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28413671/paraneoplastic-limbic-encephalitis-in-a-patient-with-extensive-disease-small-cell-lung-cancer
#17
Sebastian Ochenduszko, Bartosz Wilk, Joanna Dabrowska, Izabela Herman-Sucharska, Anna Dubis, Miroslawa Puskulluoglu
Paraneoplastic limbic encephalitis (PLE) is a rare disorder infrequently accompanying malignancy, coexisting in ~50% of the cases with small-cell lung cancer (SCLC). The pathomechanism of PLE is considered to be immune-mediated, with production of specific anti-Hu antibodies and activation of T-cells directed against onconeural antigens present on both tumor cells and neurons. We herein report the case of a 50-year-old male patient who, prior to being diagnosed with SCLC, presented with typical symptoms of PLE (seizures, subacute cognitive dysfunction with severe memory impairment, anxiety and hallucinations)...
April 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28410846/initiative-for-molecular-profiling-and-advanced-cancer-therapy-and-challenges-in-the-implementation-of-precision-medicine
#18
Apostolia-Maria Tsimberidou
In the last decade, breakthroughs in technology have improved our understanding of genomic, transcriptional, proteomic, epigenetic aberrations and immune mechanisms in carcinogenesis. Genomics and model systems have enabled the validation of novel therapeutic strategies. Based on these developments, in 2007, we initiated the IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy) study, the first personalized medicine program for patients with advanced cancer at The University of Texas MD Anderson Cancer Center...
February 10, 2017: Current Problems in Cancer
https://www.readbyqxmd.com/read/28408401/synergistic-immunostimulatory-effects-and-therapeutic-benefit-of-combined-histone-deacetylase-and-bromodomain-inhibition-in-non-small-cell-lung-cancer
#19
Dennis Adeegbe, Yan Liu, Patrick H Lizotte, Yusuke Kamihara, Amir R Aref, Christina Almonte, Ruben Dries, Yuyang Li, Shengwu Liu, Xiaoen Wang, Tiquella Warner-Hatten, Jessica Castrillon, Guo-Cheng Yuan, Neermala Poudel-Neupane, Haikuo Zhang, Jennifer L Guerriero, Shiwei Han, Mark M Awad, David A Barbie, Jerome Ritz, Simon S Jones, Peter S Hammerman, James E Bradner, Steven N Quayle, Kwok-Kin Wong
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response...
April 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28400597/indicators-of-responsiveness-to-immune-checkpoint-inhibitors
#20
Bradley D Shields, Fade Mahmoud, Erin M Taylor, Stephanie D Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel G Mackintosh, Ricky D Edmondson, Sara Shalin, Alan J Tackett
Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression...
April 11, 2017: Scientific Reports
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