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1دورية أكاديمية
المصدر: PLoS ONE, Vol 8, Iss 6 (2013)
وصف الملف: electronic resource
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2دورية أكاديمية
المصدر: PLoS ONE, Vol 7, Iss 5, p e36922 (2012)
الوصف: Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide with immunomodulatory properties. The administration of this peptide has been shown to have beneficial effects in murine models of inflammatory diseases including septic shock, rheumatoid arthritis, multiple sclerosis (MS) and Crohn's disease. However, the role of the endogenous peptide in inflammatory disease remains obscure because VIP-deficient mice were recently found to exhibit profound resistance in a model of MS. In the present study, we analyzed the response of female VIP deficient (KO) mice to intraperitoneal lipopolysaccharide (LPS) administration. We observed significant resistance to LPS in VIP KO mice, as evidenced by lower mortality and reduced tissue damage. The increased survival was associated with decreased levels of proinflammatory cytokines (TNFα, IL-6 and IL-12) in sera and peritoneal suspensions of these mice. Moreover, the expression of TNFα and IL-6 mRNA was reduced in peritoneal cells, spleens and lungs from LPS-treated VIP KO vs. WT mice, suggesting that the resistance might be mediated by an intrinsic defect in the responsiveness of immune cells to endotoxin. In agreement with this hypothesis, peritoneal cells isolated from VIP KO naive mice produced lower levels of proinflammatory cytokines in response to LPS in vitro. Finally, decreased NF-κB pathway activity in peritoneal cells was observed both in vivo and in vitro, as determined by assay of phosphorylated I-κB. The results demonstrate that female VIP KO mice exhibit resistance to LPS-induced shock, explainable in part by the presence of an intrinsic defect in the responsiveness of inflammatory cells to endotoxin.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC3355097?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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المؤلفون: Beata Berent-Maoz, Ankush Sachdeva, Thinle Chodon, Paula Cabrera, Jonathan W. Said, Allan J. Pantuck, Gardenia Cheung-Lau, Alexandra Drakaki, Izak Faiena, Begoña Comin-Anduix, Paula Kaplan-Lefko, Arie S. Belldegrun, Xiaoyan Wang, Nazy Zomorodian, Karim Chamie, Jia Pang, Adrian Bot, Mignonette H. Macabali
المصدر: Journal of Immunotherapy. 43:273-282
مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Immunology, Cancer Vaccines, Viral vector, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigens, Neoplasm, Renal cell carcinoma, Internal medicine, medicine, Humans, Immunology and Allergy, Carbonic Anhydrase IX, Adverse effect, Carcinoma, Renal Cell, Pharmacology, Leukopenia, business.industry, Disease Management, Granulocyte-Macrophage Colony-Stimulating Factor, Dendritic Cells, medicine.disease, Kidney Neoplasms, Clear cell renal cell carcinoma, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Immunotherapy, medicine.symptom, business, Progressive disease
الوصف: Expression of carbonic-anhydrase IX (CAIX) in clear cell renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion-gene construct, granulocyte-macrophage (GM) colony-stimulating factor+CAIX, delivered by an adenoviral vector (Ad) into autologous dendritic cells (DCs) in this phase 1 study. The injected immature DCs were expected to stimulate an antigen-specific immune response against CAIX expressing RCC. Three dose-escalation cohorts (5, 15, and 50×10 cells/administration) were injected intradermally q2wk×3 doses based on a 3+3 design. The primary objective was the safety of the injections. Secondary objectives were immune responses using enzyme-linked immunosorbent spot, a serum biomarker panel, and clinical response. Fifteen patients with metastatic RCC were enrolled, and 9 patients received all 3 doses. No serious adverse events were seen. There were 3 (33%) patients with grade 1 fatigue, 1 of whom subsequently experienced grade 2 fatigue. One patient (11%) experienced grade 1-2 leukopenia. Only 1 patient (11%) experienced grade 2 flu-like symptoms. Of the 9 patients who received treatment, 1 expired of progressive disease, 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have progressive disease, and 1 has completed treatment with stable disease at 27 months follow-up. Immune response measurements appeared more robust in higher dose cohorts, which appeared to be related to patients with stable disease at 3 months. These early data show that autologous immature DC-AdGMCAIX can be safely given to metastatic RCC patients without any serious adverse events with CAIX-specific immune response elicited by the treatment. These preliminary data support further study of Ad-GMCAIX, particularly with combination therapies that may enhance clinical activity.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1bd29c3067175f138603afbabf7d0d65Test
https://doi.org/10.1097/cji.0000000000000336Test -
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المؤلفون: Gabriel Abril-Rodriguez, Gardenia Cheung-Lau, Michael J. Quist, Theodore S. Nowicki, Cun-Yu Wang, Catherine S. Grasso, Antoni Ribas, Egmidio Medina, Alejandro J. Garcia, Beata Berent-Maoz, Wei Liu, Anusha Kalbasi, Jesse M. Zaretsky, Ignacio Baselga-Carretero, Cristina Puig-Saus, Jennifer Tsoi, Davis Y. Torrejon, Erkan Baloglu, William Senapedis, Siwen Hu-Lieskovan, Begoña Comin-Anduix
المصدر: Nature cancer, vol 1, iss 1
مصطلحات موضوعية: Cancer Research, Programmed cell death, T cell, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Vaccine Related, Mice, Immune system, Neoplasms, medicine, Animals, 2.1 Biological and endogenous factors, Aetiology, Immune Checkpoint Inhibitors, Cancer, Chemistry, Immunotherapy, Dendritic cell, medicine.disease, Blockade, medicine.anatomical_structure, Oncology, p21-Activated Kinases, 5.1 Pharmaceuticals, Cancer research, Immunization, Development of treatments and therapeutic interventions, Infiltration (medical), CD8
الوصف: Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b09d065e0bbc96c61ad836f7212cf1fTest
https://escholarship.org/uc/item/4p0585qjTest -
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المؤلفون: Paige Krystofinski, Jesse M. Zaretsky, Catherine S. Grasso, Gabriel Abril-Rodriguez, Antoni Ribas, Beata Berent-Maoz, Thomas Wohlwender, Anusha Kalbasi, Agustin Vega-Crespo, Siwen Hu-Lieskovan, Davis Y. Torrejon, Begoña Comin-Anduix, Giulia Parisi, Christopher M. Lee, Jennifer Tsoi, Katie M. Campbell, Gardenia Cheung-Lau, Ameya Champhekar, Pau Mascaro, Cristina Puig-Saus, Angel Garcia-Diaz
المصدر: Digital.CSIC. Repositorio Institucional del CSIC
instname
Cancer discovery, vol 10, iss 8
Cancer Discovمصطلحات موضوعية: 0301 basic medicine, CD4-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor, Drug Resistance, CD8-Positive T-Lymphocytes, Inbred C57BL, Polyethylene Glycols, Mice, 0302 clinical medicine, Interferon, Loss of Function Mutation, Neoplasms, Cytotoxic T cell, Killer Cells, 2.1 Biological and endogenous factors, Aetiology, health care economics and organizations, Cancer, Tumor, Acquired immune system, Killer Cells, Natural, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Natural, Development of treatments and therapeutic interventions, medicine.drug, Biotechnology, Agonist, Interleukin 2, medicine.drug_class, Oncology and Carcinogenesis, education, Biology, Article, Cell Line, 03 medical and health sciences, Clinical Research, Cell Line, Tumor, medicine, Animals, Humans, Gene knockout, Cell Proliferation, 5.2 Cellular and gene therapies, TLR9, Janus Kinase 1, Janus Kinase 2, Blockade, Mice, Inbred C57BL, 030104 developmental biology, Drug Resistance, Neoplasm, Toll-Like Receptor 9, Cancer research, Interleukin-2, Neoplasm, Interferons, beta 2-Microglobulin
الوصف: Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti¿PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti¿PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. Significance: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.
This study was funded in part by the Parker Institute for Cancer Immunotherapy, NIH grants R35 CA197633 and P01 CA244118, the Ressler Family Fund, and support from Ken and Donna Schultz (all to A. Ribas). D.Y. Torrejon was supported by a Young Investigator Award from ASCO, a grant from the Spanish Society of Medical Oncology for Translational Research in Reference Centers, and the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research. It has been developed within the framework of a medical doctorate at the Autonomous University of Barcelona. G. Abril-Rodriguez was supported by the Isabel & Harvey Kibel Fellowship Award and the Alan Ghitis Fellowship Award for Melanoma Research. J. Tsoi and K.M. Campbell were supported by the NIH Ruth L. Kirschstein Institutional National Research Service Award #T32-CA009120 and the UCLA Tumor Immunology Training Grant (T32CA009120). G. Parisi was supported by the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research. J.M. Zaretsky was in the UCLA Medical Scientist Training Program supported by NIH training grant GM08042. S. Hu-Lieskovan was supported by a Conquer Cancer Foundation ASCO Career Development Award, a UCLA KL2 Translational Research Award, and a Melanoma Research Alliance Young Investigator Award. Flow and mass cytometry were performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by NIH awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. The purchase of the Helios mass cytometer that was used in this work was supported, in part, by funds provided by the James B. Pendleton Charitable Trust. We want to thank Dr. Cristiana Guiducci from Dynavax and Drs. Deborah Charych and Willem Overwijk from Nektar Therapeutics for helpful guidance in the performance of in vivo studies with SD-101 and bempegaldesleukin, respectively. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39588dd9d52bb82aac65e44c0517bfbeTest
http://hdl.handle.net/10261/232405Test -
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المؤلفون: Ruixue Zhang, Siwen Hu-Lieskovan, Felix B. Salazar, Paige Krystofinski, Anna M. Wu, Jonathan Zalevsky, Sean Mackay, Catherine S. Grasso, Alejandro J. Garcia, Antoni Ribas, Jing Zhou, Adi Diab, Chantale Bernatchez, Deborah H. Charych, Jennifer Tsoi, Cristina Puig-Saus, Begoña Comin-Anduix, Giulia Parisi, Gardenia Cheung-Lau, Richard Tavaré, Justin Saco
المصدر: Nature Communications
Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020)
Nature communications, vol 11, iss 1مصطلحات موضوعية: 0301 basic medicine, Agonist, Adoptive cell transfer, medicine.drug_class, Science, T-Lymphocytes, Melanoma, Experimental, General Physics and Astronomy, Cancer immunotherapy, Inbred C57BL, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, Article, Polyethylene Glycols, Vaccine Related, 03 medical and health sciences, Experimental, Mice, 0302 clinical medicine, In vivo, Receptors, medicine, Animals, Humans, IL-2 receptor, lcsh:Science, Receptor, Melanoma, Cancer, Multidisciplinary, Chemistry, Interleukins, Receptors, Interleukin-2, General Chemistry, Adoptive Transfer, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Interleukin-2, lcsh:Q, Short exposure, B16 melanoma, Homing (hematopoietic)
الوصف: Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor βγ (IL-2Rβγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rβγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.
Adoptive cell transfer (ACT) of T cells for tumor treatment often requires IL-2 administration. Here, the authors show that a modified IL-2 cytokine (NKTR-214) can outperform IL-2 in a melanoma mouse model.وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::15124bc14ad6c895a8059f2f1211bb3aTest
http://europepmc.org/articles/PMC6994533Test -
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المؤلفون: Yanpeng Xing, Gang Deng, Michael E. Jung, Alejandro J. Garcia, Begonya Comin-Anduix, Hsiao-Wang Chen, Diana C. Márquez-Garbán, Gardenia Cheung-Lau, Nalo Hamilton, Richard J. Pietras
المصدر: J Steroid Biochem Mol Biol
مصطلحات موضوعية: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Cell, Nude, Biochemistry, CD8+T-cells, Analytical Chemistry, Mice, 0302 clinical medicine, Endocrinology, Breast cancer, Antineoplastic Agents, Immunological, Selective estrogen receptor downregulator, Receptors, Antineoplastic Combined Chemotherapy Protocols, Lymphocytes, Aromatase, Fulvestrant, Inbred BALB C, Cancer, Mice, Inbred BALB C, Tumor, biology, Estrogen Antagonists, CD8+ T-cells, medicine.anatomical_structure, Immunological, Receptors, Estrogen, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Molecular Medicine, Cytokines, Female, Immunotherapy, Development of treatments and therapeutic interventions, medicine.drug, PD-L1, Antineoplastic Agents, Hormonal, medicine.drug_class, Mice, Nude, Antineoplastic Agents, Breast Neoplasms, Article, Cell Line, 03 medical and health sciences, Endocrinology & Metabolism, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, medicine, Animals, Humans, Tumor-Infiltrating, Molecular Biology, Cell Proliferation, Hormonal, business.industry, Cell Biology, medicine.disease, Estrogen, 030104 developmental biology, Myeloid-derived suppressor cells, Cancer research, biology.protein, Myeloid-derived Suppressor Cell, Biochemistry and Cell Biology, business
الوصف: Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::201596dae33bc3b5074b2c35264ad5caTest
https://europepmc.org/articles/PMC6903431Test/ -
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المؤلفون: Theodore S. Nowicki, Siwen Hu-Lieskovan, Catherine S. Grasso, Xiaoyan Wang, Gardenia Cheung-Lau, Antoni Ribas, Ivan Perez Garcilazo, Paula Kaplan-Lefko, Alistair J. Cochran, Begoña Comin-Anduix, Anusha Kalbasi, Jia Pang, Beata Berent-Maoz, Ignacio Baselga Carretero, Justin Tran, Jennifer Tsoi, Mignonette H. Macabali, Bartosz Chmielowski, Paula Cabrera, Rong Rong Huang, Arun S. Singh
المصدر: Clinical cancer research : an official journal of the American Association for Cancer Research, vol 25, iss 7
مصطلحات موضوعية: 0301 basic medicine, Male, Cancer Research, medicine.medical_treatment, Pilot Projects, Cell therapy, Mice, 0302 clinical medicine, Antineoplastic Agents, Immunological, Neoplasms, Receptors, CTLA-4 Antigen, Lymphocytes, Gene Knock-In Techniques, Molecular Targeted Therapy, Cancer, Tumor, Melanoma, Middle Aged, Adoptive Transfer, Combined Modality Therapy, Tumor antigen, Phenotype, Immunological, Oncology, 030220 oncology & carcinogenesis, Antigen, Female, Immunotherapy, Development of treatments and therapeutic interventions, medicine.drug, Adult, Oncology and Carcinogenesis, Receptors, Antigen, T-Cell, Ipilimumab, Antineoplastic Agents, Cancer Vaccines, Article, Cell Line, Vaccine Related, 03 medical and health sciences, Young Adult, Clinical Research, Cell Line, Tumor, medicine, Animals, Humans, Oncology & Carcinogenesis, 5.2 Cellular and gene therapies, business.industry, Dendritic cell, Dendritic Cells, medicine.disease, T-Cell, Immune checkpoint, 030104 developmental biology, Cancer research, Immunization, business
الوصف: Purpose: Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab. Patients and Methods: Freshly prepared autologous NY-ESO-1–specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1–positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma. Results: Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time. Conclusions: ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d034bb7c3868fb92539e6ee64f86942fTest
https://escholarship.org/uc/item/8hg2h9nsTest -
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المؤلفون: David Berger Maneiro, Begoña Comin-Anduix, Connie B. Gilfillan, Daniel E. Speiser, Miriam Guemes-Aragon, Yaroslav Teper, Alejandro J. Garcia, Karin Schaeuble, Antoni Ribas, Julianne Schwerdtfeger, Katie M. Campbell, Gardenia Cheung-Lau, Michael Cerniglia, Christophe Martignier
المصدر: Cancer Research. 80:1697-1697
مصطلحات موضوعية: Cancer Research, Oncology, Melanoma, medicine, Cancer research, Signal transduction, Biology, medicine.disease, Cell function, Proinflammatory cytokine
الوصف: INTRODUCTION: Melanoma-acquired resistance against T cell-based immunotherapy may be mediated by alterations of their responses to inflammatory cytokines. However, the cytokine signaling pathways in cancer cells remain poorly understood. METHODS: 8 melanoma cell lines were exposed to interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) over a time course. Signaling molecules and their phosphorylated state were subsequently analyzed using mass cytometry. Briefly, cells were incubated with IFNγ (220 IU/mL), TNFα (1000 IU/mL), and both cytokines (220 IU/mL IFNγ + 200 IU/mL TNFα) for up to 48 hours. Staining was done with antibodies specific for (1) phosphorylated - STAT1(Y701), STAT3(Y707), AKT(S437), ERK1/2(T202/Y204), IKK(S176/180), NK-kbetap65 (S536), JNK (T183/T22), P38 (T180/Y182), Rb(S807/Y182), cMYC (S62), S6 (S235/S236), Histone3 (S28) and (2) non-phosphorylated - cPARP, β-catenin, CyclinB1, Ki67. Cells were read on a Helios Mass cytometer and de-barcoded using PREMESSA (R package). FlowJo was used to normalize time and eliminate calibration beads. Viable cell files were introduced to Cytobank where fold change (FC) with respect to time 0 of each protein was calculated with median intensity. The FC was exported to R for final analysis. RESULTS: All cell lines were sensitive to IFNγ/TNFα, with detectable (phosphorylated) signaling molecules. No synergistic effect was observed at any dose for IFNγ+TNFα. For the following data, numbers contained within parentheses represent the mean range of FC control vs treatment or mean standard error. pSTAT1 was significantly activated at all time points for IFNγ ([0.8, 1.0] vs [1.8, 3.6] p CONCLUSIONS: Our data show evidence for functional IFNγ/TNFα signaling in most melanoma cells. However, unexpected signaling was observed for some cell lines, possibly reflecting interpatient heterogeneity. Additional studies are necessary to understand the roles of cytokine signaling in cancer immunotherapy. Citation Format: Michael Cerniglia, Katie M. Campbell, Julianne Schwerdtfeger, Christophe Martignier, Connie B. Gilfillan, Karin Schaeuble, Gardenia Cheung-Lau, Yaroslav Teper, David Berger Maneiro, Miriam Guemes-Aragon, Alejandro J. Garcia, Daniel E. Speiser, Antoni Ribas, Begoña Comin-Anduix. Signaling pathways involved in melanoma cell functions and dedifferentiation induced by inflammatory cytokines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1697.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::215702263db2a743659b3f21a028a0a1Test
https://doi.org/10.1158/1538-7445.am2020-1697Test -
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المؤلفون: Cristina Puig-Saus, Ameya Champhekar, Siwen Hu-Lieskovan, Beata Berent-Maoz, Davis Y. Torrejon, Gabriel Abril-Rodriguez, Anusha Kalbasi, Katie M. Campbell, Gardenia Cheung-Lau, Begoña Comin-Anduix, Tom Wohlwender, Giulia Parisi, Jennifer Tsoi, Catherine S. Grasso, Antoni Ribas
المصدر: Journal of Clinical Oncology. 37:2584-2584
مصطلحات موضوعية: Cancer Research, Cas9, business.industry, Mechanism (biology), Computational biology, 03 medical and health sciences, 0302 clinical medicine, Oncology, Genome editing, 030220 oncology & carcinogenesis, Medicine, Pd 1 blockade, CRISPR, business, 030215 immunology
الوصف: 2584 Background: Mechanism-based strategies to overcome resistance to anti-PD1 therapy are urgently needed. Using CRISPR/Cas9 genome editing tools, we developed acquired resistant models through JAK1/2 and B2M loss of function (LoF) mutations in human melanoma cell lines and in the murine MC38 colon carcinoma, known for high mutational load and good response to anti-PD-1. We hypothesized that the downstream activation of the IFN-receptor pathway or the activation of natural killer (NK) cells would overcome this resistance. Methods: We studied signaling changes in four human cell lines (parental and LoFs) exposed to IFN-gamma using RNAseq. In addition, we analyzed the in-vivo antitumor activity in MC38 variants with anti-PD1 and characterized the tumor microenvironment using mass cytometry (CyTOF). Finally, we tested strategies to overcome resistance mechanisms with SD-101 (TLR-9 agonist) and bempegaldesleukin (NKTR-214, CD-122 biased agonist) with the extent of CD8 and NK1.1 depletion. Results: RNAseq differential gene expression analysis showed that the IFN-gamma induced increased expression of antigen presenting machinery, IFN-gamma signaling and chemokines (CXCL9/10) was lost in JAK1/2-LoF human melanoma cell lines. The significant antitumor activity of anti-PD-1 against MC38 parental cell line was lost in JAK1/2 and B2M LoF sublines, and CyTOF analysis revealed that anti-PD-1 therapy was unable to increase tumor CD8+ T-effectors in these LoF tumors. The intratumoral administration of SD-101 (50 μg/injection q4dx3wks) was able to overcome local resistance even in non-injected sites in JAK1/2 and IFNAR-type-I LoF tumors, and systemic administration of bempegaldesleukin (0.8 mg/kg, q9dx2, i.v.) was able to overcome resistance in B2M LoF with significantly increased survival (Table). Depletion studies showed complete abrogation of anti-tumor response with anti-NK1.1 in JAK1 LoF and B2M LoF, and partial abrogation with anti-NK1.1 or anti-CD8 in JAK2 LoF tumors. Conclusions: Even in the extreme setting of genetic resistance to PD-1 blockade by JAK1/2 LoF, resistance can be overcome by SD-101, a TLR9 agonist, while resistance of B2M LoF can be overcome by bempegaldesleukin (NKTR-214), a CD-122 biased agonist. Our findings support the testing of these rational mechanistic strategies in patients with a-PD1 resistance. [Table: see text]
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::846f6bd8d98f4a34e911c3a3f1af7081Test
https://doi.org/10.1200/jco.2019.37.15_suppl.2584Test
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