المؤلفون: Franziska Haderk, Yu-Ting Chou, Lauren Cech, Celia Fernández-Méndez, Johnny Yu, Victor Olivas, Ismail M. Meraz, Dora Barbosa Rabago, D. Lucas Kerr, Carlos Gomez, David V. Allegakoen, Juan Guan, Khyati N. Shah, Kari A. Herrington, Oghenekevwe M. Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Yashar K. Pourmoghadam, Julia K. Rotow, Caroline E. McCoach, Jonathan W. Riess, J. Silvio Gutkind, Tracy T. Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J. Kuo, Jeroen P. Roose, Wei Wu, Collin M. Blakely, Jack A. Roth, Trever G. Bivona

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/be0a7eca3725431ab19bfe58739629b9Test

المؤلفون: Shen Dong, Kamir J. Hiam-Galvez, Cody T. Mowery, Kevan C. Herold, Stephen E. Gitelman, Jonathan H. Esensten, Weihong Liu, Angela P. Lares, Ashley S. Leinbach, Michael Lee, Vinh Nguyen, Stanley J. Tamaki, Whitney Tamaki, Courtney M. Tamaki, Morvarid Mehdizadeh, Amy L. Putnam, Matthew H. Spitzer, Chun Jimmie Ye, Qizhi Tang, Jeffrey A. Bluestone

المصدر: JCI Insight, Vol 6, Iss 18 (2021)

مصطلحات موضوعية: Autoimmunity, Clinical trials, Medicine

الوصف: BACKGROUND A previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODS Patients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations’ phenotypes over time.RESULTS Multiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSION These data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATION ClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDING Sean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/7153605b428a4670a8f2035fe21e7584Test

المؤلفون: Hideho Okada, Lawrence Fong, Christine E Brown, Shilpa A Shahani, Paul R Walker, Meenal Sinha, Eric V Liu, Erin F Simonds, Edbert D Lu, Oscar Badillo, Shokoufeh Karimi, Whitney Tamaki, Chiara Rancan, Kira M Downey, Jacob Stultz, Lauren K McHenry, Nicole M Nasholm, Pavlina Chuntova, Anders Sundström, Vassilis Genoud, Leo D Wang, Fredrik J Swartling, William A Weiss, Mats Hellström

المصدر: Journal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021)

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

الوصف: Background Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.Methods We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.Results ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.Conclusions Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/9/6/e002181.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/6b195c70cb3f48339806e87479adb50bTest

المؤلفون: Jason Neidleman, Xiaoyu Luo, Julie Frouard, Guorui Xie, Feng Hsiao, Tongcui Ma, Vincent Morcilla, Ashley Lee, Sushama Telwatte, Reuben Thomas, Whitney Tamaki, Benjamin Wheeler, Rebecca Hoh, Ma Somsouk, Poonam Vohra, Jeffrey Milush, Katherine Sholtis James, Nancie M Archin, Peter W Hunt, Steven G Deeks, Steven A Yukl, Sarah Palmer, Warner C Greene, Nadia R Roan

المصدر: eLife, Vol 9 (2020)

مصطلحات موضوعية: HIV, replication-competent reservoir, tissues, CyTOF, clonal expansion, Medicine, Science, Biology (General), QH301-705.5

الوصف: The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8–10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.

وصف الملف: electronic resource

العلاقة: https://elifesciences.org/articles/60933Test; https://doaj.org/toc/2050-084XTest

الوصول الحر: https://doaj.org/article/498edfb6f058495dafa1f755ce519293Test

المؤلفون: Deborah R Caswell, Philippe Gui, Manasi K Mayekar, Emily K Law, Oriol Pich, Chris Bailey, Jesse Boumelha, D Lucas Kerr, Collin M Blakely, Tadashi Manabe, Carlos Martinez-Ruiz, Bjorn Bakker, Juan De Dios Palomino Villcas, Natalie I Vokes, Michelle Dietzen, Mihaela Angelova, Beatrice Gini, Whitney Tamaki, Paul Allegakoen, Wei Wu, Timothy J Humpton, William Hill, Mona Tomaschko, Wei-Ting Lu, Franziska Haderk, Maise Al Bakir, Ai Nagano, Francisco Gimeno-Valiente, Sophie de Carné Trécesson, Roberto Vendramin, Vittorio Barbè, Miriam Mugabo, Clare E Weeden, Andrew Rowan, Caroline E McCoach, Bruna Almeida, Mary Green, Carlos Gomez, Shigeki Nanjo, Dora Barbosa, Chris Moore, Joanna Przewrocka, James RM Black, Eva Grönroos, Alejandro Suarez-Bonnet, Simon L Priestnall, Caroline Zverev, Scott Lighterness, James Cormack, Victor Olivas, Lauren Cech, Trisha Andrews, Brandon Rule, Yuwei Jiao, Xinzhu Zhang, Paul Ashford, Cameron Durfee, Subramanian Venkatesan, Nuri Alpay Temiz, Lisa Tan, Lindsay K Larson, Prokopios P Argyris, William L Brown, Elizabeth A Yu, Julia K Rotow, Udayan Guha, Nitin Roper, Johnny Yu, Rachel I Vogel, Nicholas J Thomas, Antonio Marra, Pier Selenica, Helena Yu, Samuel F Bakhoum, Su Kit Chew, Jorge S Reis-Filho, Mariam Jamal-Hanjani, Karen H Vousden, Nicholas McGranahan, Eliezer M Van Allen, Nnennaya Kanu, Reuben S Harris, Julian Downward, Trever G Bivona, Charles Swanton

مصطلحات موضوعية: Model organisms, Tumour Biology, Gene Expression, Genetics & Genomics, Genome Integrity & Repair, Humans, Animals, Mice, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Mutation, Up-Regulation, ErbB Receptors, Cytidine Deaminase, Minor Histocompatibility Antigens, Swanton CC2041, Vousden CC2073, Downward CC2097, HP, BRF, Adekoya, Adebambo, Horwood, Antony, Nye, Emma, Coelho Almeida, Bruna, Stone

الوصف: In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

العلاقة: https://figshare.com/articles/journal_contribution/The_role_of_APOBEC3B_in_lung_tumor_evolution_and_targeted_cancer_therapy_resistance_/25020116Test

الإتاحة: https://doi.org/10.25418/crick.25020116.v1Test
https://figshare.com/articles/journal_contribution/The_role_of_APOBEC3B_in_lung_tumor_evolution_and_targeted_cancer_therapy_resistance_/25020116Test

المؤلفون: Byungjin Hwang, David S. Lee, Whitney Tamaki, Yang Sun, Anton Ogorodnikov, George C. Hartoularos, Aidan Winters, Bertrand Z. Yeung, Kristopher L. Nazor, Yun S. Song, Eric D. Chow, Matthew H. Spitzer, Chun Jimmie Ye

الوصف: Single-cell combinatorial indexed cytometry sequencing (SCITO-seq) combines split-pool indexing and droplet-based single cell sequencing for single-cell protein profiling. This repository contains codes to reproduce figures in the SCITO-seq paper. Additional data can also be found in https://github.com/yelabucsf/SCITO-seq_ManuscriptTest.

العلاقة: https://zenodo.org/communities/single_cell_rna_seq_analysisTest; https://zenodo.org/record/4988182Test; https://doi.org/10.5281/zenodo.4988182Test; oai:zenodo.org:4988182

الإتاحة: https://doi.org/10.5281/zenodo.4988182Test
https://doi.org/10.5281/zenodo.4988181Test
https://zenodo.org/record/4988182Test

المؤلفون: Meenal Sinha, Courtney Betts, Li Zhang, Madeline J Griffith, Isabelle Solman, Brandon Chen, Eric Liu, Whitney Tamaki, Jacob Stultz, Jaqueline Marquez, Shamilene Sivagnanam, Alexander Cheung, Denise Pener, Anne Fahlman, Erin Taber, Kimberly Lerner, Matthew Crocker, Kendra Todd, Brindha Rajagopalan, Clarisha Ware, Mark Bridge, Johnson Vo, Hannah Dragomanovich, Julie Sudduth-Klinger, Gina Vaccaro, Charles D Lopez, Margaret Tempero, Lisa M Coussens, Lawrence Fong

المصدر: Journal for immunotherapy of cancer, vol 11, iss 1

مصطلحات موضوعية: Cancer Research, Immunology, Programmed Cell Death 1 Receptor, Clinical Trials and Supportive Activities, Antineoplastic Agents, Adenocarcinoma, Lymphocyte Activation, Tyrosine Protein Kinase Inhibitors, Immunomodulation, Pancreatic Cancer, Rare Diseases, Immunologic, Clinical Research, Receptors, Tumor Microenvironment, Immunology and Allergy, Humans, 6.2 Cellular and gene therapies, Cancer, Pharmacology, Carcinoma, Evaluation of treatments and therapeutic interventions, Stem Cell Research, Gemcitabine, Pancreatic Neoplasms, Orphan Drug, Good Health and Well Being, Oncology, Pancreatic Ductal, 6.1 Pharmaceuticals, Molecular Medicine, Immunotherapy, Digestive Diseases, Carcinoma, Pancreatic Ductal

الوصف: BackgroundIn preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.MethodsPreviously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.ResultsIn the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+EOMES+) CD8+T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.ConclusionIbrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration numberNCT02562898.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2234572939e8210e175f36091a0a956dTest
https://escholarship.org/uc/item/22n0d044Test

المؤلفون: Kamir J Hiam-Galvez, Courtney M Tamaki, Weihong Liu, Cody T. Mowery, Chun Jimmie Ye, Ashley S. Leinbach, Stephen E. Gitelman, Shen Dong, Angela P. Lares, Kevan C. Herold, Michael R. Lee, Morvarid Mehdizadeh, Vinh Son Nguyen, Jonathan H. Esensten, Amy L. Putnam, Qizhi Tang, Jeffrey A. Bluestone, Matthew H. Spitzer, Stanley Tamaki, Whitney Tamaki

المصدر: JCI Insight

مصطلحات موضوعية: Adult, Male, Time Factors, Combination therapy, Cell Survival, medicine.medical_treatment, T cell, T cells, Autoimmunity, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, medicine.disease_cause, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, Cell therapy, Young Adult, Immune system, medicine, Humans, Hypoglycemic Agents, Insulin, Cytotoxic T cell, Clinical Trials, Lymphocyte Count, Glycated Hemoglobin, C-Peptide, business.industry, Diabetes, General Medicine, Immunotherapy, Combined Modality Therapy, Recombinant Proteins, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Immunology, Interleukin-2, Natural Killer T-Cells, Female, Clinical Medicine, Transcriptome, business, CD8

الوصف: BACKGROUND A previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells. METHODS Patients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations’ phenotypes over time. RESULTS Multiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations. CONCLUSION These data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity. TRIAL REGISTRATION ClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial). FUNDING Sean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::983c76b05789c8ccfe05b979c8255f10Test
https://doi.org/10.1172/jci.insight.147474Test

المؤلفون: Bertrand Z. Yeung, Matthew H. Spitzer, Aidan F. Winters, Whitney Tamaki, Yun S. Song, Byungjin Hwang, Yang Sun, Anton Ogorodnikov, Chun Jimmie Ye, David Lee, Kristopher L. Nazor, Eric D. Chow, George C. Hartoularos

المصدر: Nature methods, vol 18, iss 8
Nat Methods

مصطلحات موضوعية: Technology, Sequence analysis, Microfluidics, Cell, genetic processes, Computational biology, Biochemistry, Medical and Health Sciences, Article, Transcriptome, medicine, Genetics, Humans, Mass cytometry, natural sciences, Molecular Biology, Chemistry, Oligonucleotide, Sequence Analysis, RNA, Gene Expression Profiling, Human Genome, High-Throughput Nucleotide Sequencing, Cell Biology, Biological Sciences, Flow Cytometry, Gene expression profiling, medicine.anatomical_structure, Case-Control Studies, RNA, Generic health relevance, Single-Cell Analysis, Cytometry, Sequence Analysis, Biotechnology, Developmental Biology

الوصف: The development of DNA-barcoded antibodies to tag cell surface molecules has enabled the use of droplet-based single-cell sequencing (dsc-seq) to profile protein abundances from thousands of cells simultaneously. As compared to flow and mass cytometry, the high per cell cost of current dsc-seq-based workflows precludes their use in clinical applications and large-scale pooled screens. Here, we introduce SCITO-seq, a workflow that uses splint oligonucleotides (oligos) to enable combinatorially indexed dsc-seq of DNA-barcoded antibodies from over 105 cells per reaction using commercial microfluidics. By encoding sample barcodes into splint oligos, we demonstrate that multiplexed SCITO-seq produces reproducible estimates of cellular composition and surface protein expression comparable to those from mass cytometry. We further demonstrate two modified splint oligo designs that extend SCITO-seq to achieve compatibility with commercial DNA-barcoded antibodies and simultaneous expression profiling of the transcriptome and surface proteins from the same cell. These results demonstrate SCITO-seq as a flexible and ultra-high-throughput platform for sequencing-based single-cell protein and multimodal profiling.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a00be87dc685c92548a45dedb906c7f9Test
https://escholarship.org/uc/item/4h28g221Test

المؤلفون: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely

المصدر: Cancer Research. 82:3808-3808

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Introduction: Single-cell RNA sequencing of dissociated tumors enables the profiling of cellular states in fine detail, but erases the cellular organization of the analyzed tissue. Spatially resolved transcriptomics (SRT) using 10X Genomics’ Visium platform combines histological staining and RNA sequencing by capturing each transcript across spatially barcoded microarrays. SRT yields gene-expression matrices resolved within 55-micron array spots, and creates opportunities to explore how lung biology is affected by lung adenocarcinoma and how tumor cells and the proximal microenvironment are modulated by targeted therapy. Methods: SRT reactions (n=8) were performed on surgical specimens from human lung adenocarcinomas driven by kinase domain mutations of EGFR (exon 19 deletion, L858R point mutation, exon 20 insertion). SRT reactions analyzed primary lung cancer (n=5) or paired tumor-adjacent lung tissues (n=3). Results: 28458 array spots were recorded across all samples, and array spots captured a median of 5800 total transcripts and a median of 2416 unique transcripts. Single marker gene expression and unsupervised clustering across array spots corresponded with histological annotations of lung structures and adenocarcinoma. Integration of single-cell RNA sequencing data from lung adenocarcinoma specimens permitted mapping and quantification of 15 major cell types, including cancer cells, T- and B- lymphocytes, macrophages, dendritic cells, fibroblasts, and endothelial cells. Compared with paired tumor-adjacent lung tissues, adenocarcinoma tissues contained fibroblast-enriched desmoplasia and B-cell enriched tertiary lymphoid structures. In a clinical case with resistance to Osimertinib, the standard tyrosine kinase inhibitor, gene signature analysis of cancer-containing array spots revealed enrichment of gap-junction, fatty acid metabolism, and kynurenine pathway signatures compared to treatment naïve array spots. Conclusion: This pilot study demonstrates the feasibility of using SRT in lung adenocarcinoma. Paired with a single-cell atlas of lung adenocarcinoma during targeted therapy, this approach enables hypothesis-generation to investigate the alterations of tumor and tumor microenvironmental architecture in relation to targeted therapy. Citation Format: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely. Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3808.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::6e9f33862ea8e145df3e12fd4ac83a5aTest
https://doi.org/10.1158/1538-7445.am2022-3808Test