المؤلفون: Jonathan K. M. Lim, Arash Samiei, Alberto Delaidelli, Jessica Oliveira de Santis, Vanessa Brinkmann, Christopher J. Carnie, Daniel Radiloff, Laura Hruby, Alisa Kahler, Jordan Cran, Gabriel Leprivier, Poul H. Sorensen

المصدر: Cell Death and Disease, Vol 15, Iss 7, Pp 1-10 (2024)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a stress-responsive hub that inhibits the translation elongation factor eEF2, and consequently mRNA translation elongation, in response to hypoxia and nutrient deprivation. EEF2K is also involved in the response to DNA damage but its role in response to DNA crosslinks, as induced by cisplatin, is not known. Here we found that eEF2K is critical to mediate the cellular response to cisplatin. We uncovered that eEF2K deficient cells are more resistant to cisplatin treatment. Mechanistically, eEF2K deficiency blunts the activation of the DNA damage response associated ATM and ATR pathways, in turn preventing p53 activation and therefore compromising induction of cisplatin-induced apoptosis. We also report that loss of eEF2K delays the resolution of DNA damage triggered by cisplatin, suggesting that eEF2K contributes to DNA damage repair in response to cisplatin. In support of this, our data shows that eEF2K promotes the expression of the DNA repair protein ERCC1, critical for the repair of cisplatin-caused DNA damage. Finally, using Caenorhabditis elegans as an in vivo model, we find that deletion of efk-1, the worm eEF2K ortholog, mitigates the induction of germ cell death in response to cisplatin. Together, our data highlight that eEF2K represents an evolutionary conserved mediator of the DNA damage response to cisplatin which promotes p53 activation to induce cell death, or alternatively facilitates DNA repair, depending on the extent of DNA damage.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/6835837b84d7441fa2ee38d01cd997d9Test

المؤلفون: Arash Nabbi, Pengbo Beck, Alberto Delaidelli, Derek A. Oldridge, Sumedha Sudhaman, Kelsey Zhu, S. Y. Cindy Yang, David T. Mulder, Jeffrey P. Bruce, Joseph N. Paulson, Pichai Raman, Yuankun Zhu, Adam C. Resnick, Poul H. Sorensen, Martin Sill, Sebastian Brabetz, Sander Lambo, David Malkin, Pascal D. Johann, Marcel Kool, David T. W. Jones, Stefan M. Pfister, Natalie Jäger, Trevor J. Pugh

المصدر: Genome Medicine, Vol 15, Iss 1, Pp 1-24 (2023)

مصطلحات موضوعية: Paediatric neuro-oncology, Immunogenomics, CNS tumours, Tumour microenvironment, Neuroblastoma, Medicine, Genetics, QH426-470

الوصف: Abstract Background Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers. Methods To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets. Results Within pedNST, we uncovered four broad immune clusters: Paediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Desert (17%). We validated these clusters using immunohistochemistry, methylation immune inference and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Conclusions Given the heterogeneity of immune infiltration within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-994XTest

الوصول الحر: https://doaj.org/article/55f18503cc5b446bb5969c8df01fb686Test

المؤلفون: Theruvath, Johanna, Menard, Marie, Smith, Benjamin AH, Linde, Miles H, Coles, Garry L, Dalton, Guillermo Nicolas, Wu, Wei, Kiru, Louise, Delaidelli, Alberto, Sotillo, Elena, Silberstein, John L, Geraghty, Anna C, Banuelos, Allison, Radosevich, Molly Thomas, Dhingra, Shaurya, Heitzeneder, Sabine, Tousley, Aidan, Lattin, John, Xu, Peng, Huang, Jing, Nasholm, Nicole, He, Andy, Kuo, Tracy C, Sangalang, Emma RB, Pons, Jaume, Barkal, Amira, Brewer, Rachel E, Marjon, Kristopher D, Vilches-Moure, Jose G, Marshall, Payton L, Fernandes, Ricardo, Monje, Michelle, Cochran, Jennifer R, Sorensen, Poul H, Daldrup-Link, Heike E, Weissman, Irving L, Sage, Julien, Majeti, Ravindra, Bertozzi, Carolyn R, Weiss, William A, Mackall, Crystal L, Majzner, Robbie G

المصدر: Nature Medicine. 28(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Pediatric Research Initiative, Pediatric, Neurosciences, Pediatric Cancer, Rare Diseases, Orphan Drug, Cancer, Neuroblastoma, Animals, Bone Neoplasms, CD47 Antigen, Cell Line, Tumor, Humans, Immunotherapy, Mice, Neoplasm Recurrence, Local, Phagocytosis, Tumor Microenvironment, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences

الوصف: The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5nz6n240Test

المؤلفون: Brian Mooney, Gian Luca Negri, Taras Shyp, Alberto Delaidelli, Hai-Feng Zhang, Sandra E. Spencer Miko, Amber K. Weiner, Alexander B. Radaoui, Rawan Shraim, Michael M. Lizardo, Christopher S. Hughes, Amy Li, Amal M. El-Naggar, Melanie Rouleau, Wei Li, Dimiter S. Dimitrov, Raushan T. Kurmasheva, Peter J. Houghton, Sharon J. Diskin, John M. Maris, Gregg B. Morin, Poul H. Sorensen

مصطلحات موضوعية: Cancer, Therapeutic Research and Development, Immuno-oncology, Methods and Technology, Immunotherapy, Pediatric Cancers, Preclinical Models, Xenograft models, Protein Technologies, Sarcomas, Translational Research

الوصف: Surface protein annotation based on COMPARTMENTS and GO

العلاقة: https://figshare.com/articles/journal_contribution/Supplementary_Table_S2_from_Surface_and_Global_Proteome_Analyses_Identify_ENPP1_and_Other_Surface_Proteins_as_Actionable_Immunotherapeutic_Targets_in_Ewing_Sarcoma/25324148Test

الإتاحة: https://doi.org/10.1158/1078-0432.25324148.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_Table_S2_from_Surface_and_Global_Proteome_Analyses_Identify_ENPP1_and_Other_Surface_Proteins_as_Actionable_Immunotherapeutic_Targets_in_Ewing_Sarcoma/25324148Test

المؤلفون: Brian Mooney, Gian Luca Negri, Taras Shyp, Alberto Delaidelli, Hai-Feng Zhang, Sandra E. Spencer Miko, Amber K. Weiner, Alexander B. Radaoui, Rawan Shraim, Michael M. Lizardo, Christopher S. Hughes, Amy Li, Amal M. El-Naggar, Melanie Rouleau, Wei Li, Dimiter S. Dimitrov, Raushan T. Kurmasheva, Peter J. Houghton, Sharon J. Diskin, John M. Maris, Gregg B. Morin, Poul H. Sorensen

مصطلحات موضوعية: Cancer, Therapeutic Research and Development, Immuno-oncology, Methods and Technology, Immunotherapy, Pediatric Cancers, Preclinical Models, Xenograft models, Protein Technologies, Sarcomas, Translational Research

الوصف: Correlation between surfaceome and global proteome datasets.

العلاقة: https://figshare.com/articles/journal_contribution/Supplementary_Figure_S4_from_Surface_and_Global_Proteome_Analyses_Identify_ENPP1_and_Other_Surface_Proteins_as_Actionable_Immunotherapeutic_Targets_in_Ewing_Sarcoma/25324169Test

الإتاحة: https://doi.org/10.1158/1078-0432.25324169.v1Test
https://figshare.com/articles/journal_contribution/Supplementary_Figure_S4_from_Surface_and_Global_Proteome_Analyses_Identify_ENPP1_and_Other_Surface_Proteins_as_Actionable_Immunotherapeutic_Targets_in_Ewing_Sarcoma/25324169Test

المؤلفون: Betty Yao, Alberto Delaidelli, Hannes Vogel, Poul H. Sorensen

المصدر: Current Oncology, Vol 30, Iss 5, Pp 5024-5046 (2023)

مصطلحات موضوعية: tumour immune microenvironment, pediatric brain tumour, immunotherapy, medulloblastoma, pediatric high-grade glioma, tumour-infiltrating lymphocytes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: In spite of recent advances in tumour molecular subtyping, pediatric brain tumours (PBTs) remain the leading cause of cancer-related deaths in children. While some PBTs are treatable with favourable outcomes, recurrent and metastatic disease for certain types of PBTs remains challenging and is often fatal. Tumour immunotherapy has emerged as a hopeful avenue for the treatment of childhood tumours, and recent immunotherapy efforts have been directed towards PBTs. This strategy has the potential to combat otherwise incurable PBTs, while minimizing off-target effects and long-term sequelae. As the infiltration and activation states of immune cells, including tumour-infiltrating lymphocytes and tumour-associated macrophages, are key to shaping responses towards immunotherapy, this review explores the immune landscape of the developing brain and discusses the tumour immune microenvironments of common PBTs, with hopes of conferring insights that may inform future treatment design.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1718-7729/30/5/379Test; https://doaj.org/toc/1198-0052Test; https://doaj.org/toc/1718-7729Test

الوصول الحر: https://doaj.org/article/d3be6e31314e401f98284991090f1880Test

المؤلفون: Alberto Delaidelli, Alessandro Moiraghi

المصدر: Brain Sciences, Vol 14, Iss 3, p 224 (2024)

مصطلحات موضوعية: n/a, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Brain tumors represent some of the most aggressive malignancies [...]

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2076-3425/14/3/224Test; https://doaj.org/toc/2076-3425Test

الوصول الحر: https://doaj.org/article/6d1139b9cea34cd1aa16641eef6d84e2Test

المؤلفون: Nabbi, Arash, Beck, Pengbo, Delaidelli, Alberto, Oldridge, Derek A., Sudhaman, Sumedha, Zhu, Kelsey, Yang, S. Y. Cindy, Mulder, David T., Bruce, Jeffrey P., Paulson, Joseph N., Raman, Pichai, Zhu, Yuankun, Resnick, Adam C., Sorensen, Poul H., Sill, Martin, Brabetz, Sebastian, Lambo, Sander, Malkin, David, Johann, Pascal D., Kool, Marcel, Jones, David T. W., Pfister, Stefan M., Jäger, Natalie, Pugh, Trevor J.

المساهمون: Terry Fox Research Institute, NHLBI Division of Intramural Research, Parker Institute for Cancer Immunotherapy, Deutsche Krebshilfe

المصدر: Genome Medicine ; volume 15, issue 1 ; ISSN 1756-994X

مصطلحات موضوعية: Genetics (clinical), Genetics, Molecular Biology, Molecular Medicine

الوصف: Background Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers. Methods To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets. Results Within pedNST, we uncovered four broad immune clusters: Paediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Desert (17%). We validated these clusters using immunohistochemistry, methylation immune inference and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Conclusions Given the heterogeneity of immune infiltration within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

الإتاحة: https://doi.org/10.1186/s13073-023-01219-xTest

المؤلفون: Yamada-Hunter, Sean A., Theruvath, Johanna, McIntosh, Brianna J., Freitas, Katherine A., Lin, Frank, Radosevich, Molly T., Leruste, Amaury, Dhingra, Shaurya, Martinez-Velez, Naiara, Xu, Peng, Huang, Jing, Delaidelli, Alberto, Desai, Moksha H., Good, Zinaida, Polak, Roel, May, Audre, Labanieh, Louai, Bjelajac, Jeremy, Murty, Tara, Ehlinger, Zach

المصدر: Nature; Jun2024, Vol. 630 Issue 8016, p457-465, 9p

مستخلص: Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.Combination of TCR or CAR T cells expressing the engineered CD47 variant 47E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment. [ABSTRACT FROM AUTHOR]

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المؤلفون: David M Barrett, Daniel Martinez, Tiffany Smith, Jessica B Foster, Crystal Griffin, Jo Lynne Rokita, Allison Stern, Cameron Brimley, Komal Rathi, Maria V Lane, Samantha N Buongervino, Peter J Madsen, Alberto Delaidelli, Poul H Sorensen, Robert J Wechsler-Reya, Katalin Karikó, Phillip B Storm, Adam C Resnick, John M Maris, Kristopher R Bosse

المصدر: Journal for ImmunoTherapy of Cancer, Vol 10, Iss 9 (2022)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.Methods We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.Results We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.Conclusion Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/10/9/e004450.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/e7606fcfe47343a78a08e0f4943daef3Test