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  1. Article ; Online: Spatial transcriptomics reveals distinct tissue niches linked with steroid responsiveness in acute gastrointestinal GVHD.

    Patel, Bidish K / Raabe, Michael J / Lang, Evan R / Song, Yuhui / Lu, Chenyue / Deshpande, Vikram / Nieman, Linda T / Aryee, Martin J / Chen, Yi-Bin / Ting, David T / DeFilipp, Zachariah

    Blood

    2023  Volume 142, Issue 21, Page(s) 1831–1844

    Abstract: Severe acute graft-versus-host disease (aGVHD) is associated with significant mortality and morbidity, especially in steroid-resistant (SR) cases. Spatial transcriptomic technology can elucidate tissue-based interactions in vivo and possibly identify ... ...

    Abstract Severe acute graft-versus-host disease (aGVHD) is associated with significant mortality and morbidity, especially in steroid-resistant (SR) cases. Spatial transcriptomic technology can elucidate tissue-based interactions in vivo and possibly identify predictors of treatment response. Tissue sections from 32 treatment-naïve patients with biopsy-confirmed lower gastrointestinal (GI) aGVHD were obtained. The GeoMx digital spatial profiler was used to capture transcriptome profiles of >18 000 genes from different foci of immune infiltrates, colonic epithelium, and vascular endothelium. Each tissue compartment sampled showed 2 distinct clusters that were analyzed for differential expression and spatially resolved correlation of gene signatures. Classic cell-mediated immunity signatures, normal differentiated epithelial cells, and inflamed vasculature dominated foci sampled from steroid-sensitive cases. In contrast, a neutrophil predominant noncanonical inflammation with regenerative epithelial cells and some indication of angiogenic endothelial response was overrepresented in areas from SR cases. Evaluation of potential prognostic biomarkers identified ubiquitin specific peptidase 17-like (USP17L) family of genes as being differentially expressed in immune cells from patients with worsened survival. In summary, we demonstrate distinct tissue niches with unique gene expression signatures within lower GI tissue from patients with aGVHD and provide evidence of a potential prognostic biomarker.
    MeSH term(s) Humans ; Transcriptome ; Graft vs Host Disease/drug therapy ; Graft vs Host Disease/genetics ; Immunity, Cellular ; Steroids/therapeutic use ; Intestinal Mucosa ; Acute Disease ; Hematopoietic Stem Cell Transplantation
    Chemical Substances Steroids
    Language English
    Publishing date 2023-09-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023020644
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Dysregulated Repeat Element Viral-like Immune Response in Hepatocellular Carcinoma.

    Coley, Avril K / Lu, Chenyue / Pankaj, Amaya / Emmett, Matthew J / Lang, Evan R / Song, Yuhui / Xu, Katherine H / Xu, Nova / Patel, Bidish K / Chougule, Abhijit / Nieman, Linda T / Aryee, Martin J / Ferrone, Cristina R / Deshpande, Vikram / Franses, Joseph W / Ting, David T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Purpose: Dysregulation of viral-like repeat RNAs are a common feature across many malignancies that are linked with immunological response, but the characterization of these in hepatocellular carcinoma (HCC) is understudied. In this study, we performed ... ...

    Abstract Purpose: Dysregulation of viral-like repeat RNAs are a common feature across many malignancies that are linked with immunological response, but the characterization of these in hepatocellular carcinoma (HCC) is understudied. In this study, we performed RNA
    Experimental design: RNA-ISH for LINE1, HERV-K, HERV-H, and HSATII repeats and IHC for T-cell, Treg, B-cell, macrophage, and immune checkpoint markers were performed on 43 resected HCC specimens. Spatial transcriptomics on tumor and vessel regions of interest was performed on 28 specimens from the same cohort.
    Results: High HERV-K and high LINE1 expression were both associated with worse overall survival. There was a positive correlation between LINE1 expression and FOXP3 T-regulatory cells (r = 0.51 p < 0.001) as well as expression of the TIM3 immune checkpoint (r = 0.34, p = 0.03). Spatial transcriptomic profiling of HERV-K high and LINE-1 high tumors identified elevated expression of multiple genes previously associated with epithelial mesenchymal transition, cellular proliferation, and worse overall prognosis in HCC including SSX1, MAGEC2, and SPINK1.
    Conclusion: Repeat RNAs may serve as useful prognostic biomarkers in HCC and may also serve as novel therapeutic targets. Additional study is needed to understand the mechanisms by which repeat RNAs impact HCC tumorigenesis.
    Language English
    Publishing date 2023-12-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.04.570014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Active RB causes visible changes in nuclear organization.

    Krishnan, Badri / Yasuhara, Takaaki / Rumde, Purva / Stanzione, Marcello / Lu, Chenyue / Lee, Hanjun / Lawrence, Michael S / Zou, Lee / Nieman, Linda T / Sanidas, Ioannis / Dyson, Nicholas J

    The Journal of cell biology

    2022  Volume 221, Issue 3

    Abstract: RB restricts G1/S progression by inhibiting E2F. Here, we show that sustained expression of active RB, and prolonged G1 arrest, causes visible changes in chromosome architecture that are not directly associated with E2F inhibition. Using FISH probes ... ...

    Abstract RB restricts G1/S progression by inhibiting E2F. Here, we show that sustained expression of active RB, and prolonged G1 arrest, causes visible changes in chromosome architecture that are not directly associated with E2F inhibition. Using FISH probes against two euchromatin RB-associated regions, two heterochromatin domains that lack RB-bound loci, and two whole-chromosome probes, we found that constitutively active RB (ΔCDK-RB) promoted a more diffuse, dispersed, and scattered chromatin organization. These changes were RB dependent, were driven by specific isoforms of monophosphorylated RB, and required known RB-associated activities. ΔCDK-RB altered physical interactions between RB-bound genomic loci, but the RB-induced changes in chromosome architecture were unaffected by dominant-negative DP1. The RB-induced changes appeared to be widespread and influenced chromosome localization within nuclei. Gene expression profiles revealed that the dispersion phenotype was associated with an increased autophagy response. We infer that, after cell cycle arrest, RB acts through noncanonical mechanisms to significantly change nuclear organization, and this reorganization correlates with transitions in cellular state.
    MeSH term(s) Autophagy ; Cell Cycle Checkpoints ; Cell Line ; Cell Nucleus/metabolism ; Chromatin/metabolism ; DNA Topoisomerases, Type I/metabolism ; Histone Deacetylases/metabolism ; Humans ; Mutation/genetics ; Phenotype ; Protein Binding ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism
    Chemical Substances Chromatin ; Retinoblastoma Protein ; Histone Deacetylases (EC 3.5.1.98) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
    Language English
    Publishing date 2022-01-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.202102144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis.

    Thomas, Molly Fisher / Slowikowski, Kamil / Manakongtreecheep, Kasidet / Sen, Pritha / Samanta, Nandini / Tantivit, Jessica / Nasrallah, Mazen / Zubiri, Leyre / Smith, Neal P / Tirard, Alice / Ramesh, Swetha / Arnold, Benjamin Y / Nieman, Linda T / Chen, Jonathan H / Eisenhaure, Thomas / Pelka, Karin / Song, Yuhui / Xu, Katherine H / Jorgji, Vjola /
    Pinto, Christopher J / Sharova, Tatyana / Glasser, Rachel / Chan, PuiYee / Sullivan, Ryan J / Khalili, Hamed / Juric, Dejan / Boland, Genevieve M / Dougan, Michael / Hacohen, Nir / Li, Bo / Reynolds, Kerry L / Villani, Alexandra-Chloé

    Nature medicine

    2024  

    Abstract: Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, ...

    Abstract Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAE
    Language English
    Publishing date 2024-05-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-024-02895-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Selective targeting of MYC mRNA by stabilized antisense oligonucleotides.

    Gill, Taylor / Wang, Haichuan / Bandaru, Raj / Lawlor, Matthew / Lu, Chenyue / Nieman, Linda T / Tao, Junyan / Zhang, Yixian / Anderson, Daniel G / Ting, David T / Chen, Xin / Bradner, James E / Ott, Christopher J

    Oncogene

    2021  Volume 40, Issue 47, Page(s) 6527–6539

    Abstract: MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we ... ...

    Abstract MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5'- and 3'-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.
    MeSH term(s) Animals ; Apoptosis ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation ; Female ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Mice ; Mice, Inbred C57BL ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/pharmacology ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; RNA Stability ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances MYC protein, human ; Oligonucleotides, Antisense ; Proto-Oncogene Proteins c-myc
    Language English
    Publishing date 2021-10-14
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-021-02053-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice.

    Richardson, Leland G / Nieman, Linda T / Stemmer-Rachamimov, Anat O / Zheng, Xijin S / Stafford, Khalifa / Nagashima, Hiroaki / Miller, Julie J / Kiyokawa, Juri / Ting, David T / Wakimoto, Hiroaki / Cahill, Daniel P / Choi, Bryan D / Curry, William T

    Oncoimmunology

    2020  Volume 9, Issue 1, Page(s) 1806662

    Abstract: The metabolic gene isocitrate dehydrogenase 1 ( ...

    Abstract The metabolic gene isocitrate dehydrogenase 1 (
    MeSH term(s) Animals ; Brain Neoplasms/genetics ; Glioma/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Mice ; Mutation ; T-Lymphocytes, Regulatory
    Chemical Substances Isocitrate Dehydrogenase (EC 1.1.1.41)
    Language English
    Publishing date 2020-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-4011
    ISSN (online) 2162-402X
    ISSN 2162-4011
    DOI 10.1080/2162402X.2020.1806662
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Differential Kinase Activity Across Prostate Tumor Compartments Defines Sensitivity to Target Inhibition.

    Karabacak, Nezihi Murat / Zheng, Yu / Dubash, Taronish D / Burr, Risa / Micalizzi, Douglas S / Wittner, Ben S / Lin, Maoxuan / Wiley, Devon F / Comaills, Valentine / Emmons, Erin / Niederhoffer, Kira L / Ho, Uyen / Ukleja, Jacob / Che, Dante / Stowe, Hannah / Nieman, Linda T / Haas, Wilhelm / Stott, Shannon L / Lawrence, Michael S /
    Ting, David T / Miyamoto, David T / Haber, Daniel A / Toner, Mehmet / Maheswaran, Shyamala

    Cancer research

    2022  Volume 82, Issue 6, Page(s) 1084–1097

    Abstract: Cancer therapy often results in heterogeneous responses in different metastatic lesions in the same patient. Inter- and intratumor heterogeneity in signaling within various tumor compartments and its impact on therapy are not well characterized due to ... ...

    Abstract Cancer therapy often results in heterogeneous responses in different metastatic lesions in the same patient. Inter- and intratumor heterogeneity in signaling within various tumor compartments and its impact on therapy are not well characterized due to the limited sensitivity of single-cell proteomic approaches. To overcome this barrier, we applied single-cell mass cytometry with a customized 26-antibody panel to PTEN-deleted orthotopic prostate cancer xenograft models to measure the evolution of kinase activities in different tumor compartments during metastasis or drug treatment. Compared with primary tumors and circulating tumor cells (CTC), bone metastases, but not lung and liver metastases, exhibited elevated PI3K/mTOR signaling and overexpressed receptor tyrosine kinases (RTK) including c-MET protein. Suppression of c-MET impaired tumor growth in the bone. Intratumoral heterogeneity within tumor compartments also arose from highly proliferative EpCAM-high epithelial cells with increased PI3K and mTOR kinase activities coexisting with poorly proliferating EpCAM-low mesenchymal populations with reduced kinase activities; these findings were recapitulated in epithelial and mesenchymal CTC populations in patients with metastatic prostate and breast cancer. Increased kinase activity in EpCAM-high cells rendered them more sensitive to PI3K/mTOR inhibition, and drug-resistant EpCAM-low populations with reduced kinase activity emerged over time. Taken together, single-cell proteomics indicate that microenvironment- and cell state-dependent activation of kinase networks create heterogeneity and differential drug sensitivity among and within tumor populations across different sites, defining a new paradigm of drug responses to kinase inhibitors.
    Significance: Single-cell mass cytometry analyses provide insights into the differences in kinase activities across tumor compartments and cell states, which contribute to heterogeneous responses to targeted therapies.
    MeSH term(s) Animals ; Cell Line, Tumor ; Epithelial Cell Adhesion Molecule ; Humans ; Male ; Phosphatidylinositol 3-Kinases/metabolism ; Prostatic Neoplasms/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Proteomics ; TOR Serine-Threonine Kinases/metabolism ; Tumor Microenvironment
    Chemical Substances Epithelial Cell Adhesion Molecule ; Protein Kinase Inhibitors ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2022-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-21-2609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response.

    Chen, Jonathan H / Nieman, Linda T / Spurrell, Maxwell / Jorgji, Vjola / Richieri, Peter / Xu, Katherine H / Madhu, Roopa / Parikh, Milan / Zamora, Izabella / Mehta, Arnav / Nabel, Christopher S / Freeman, Samuel S / Pirl, Joshua D / Lu, Chenyue / Meador, Catherine B / Barth, Jaimie L / Sakhi, Mustafa / Tang, Alexander L / Sarkizova, Siranush /
    Price, Colles / Fernandez, Nicolas F / Emanuel, George / He, Jiang / Raay, Katrina Van / Reeves, Jason W / Yizhak, Keren / Hofree, Matan / Shih, Angela / Sade-Feldman, Moshe / Boland, Genevieve M / Pelka, Karin / Aryee, Martin / Korsunsky, Ilya / Mino-Kenudson, Mari / Gainor, Justin F / Hacohen, Nir

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting ... ...

    Abstract The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.04.535379
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Compact beveled fiber optic probe design for enhanced depth discrimination in epithelial tissues.

    Nieman, Linda T / Jakovljevic, Marko / Sokolov, Konstantin

    Optics express

    2009  Volume 17, Issue 4, Page(s) 2780–2796

    Abstract: We report the development and evaluation of a simple compact probe that incorporates multiple beveled fibers for depth sensitive detection of spectroscopic signals in vivo. We evaluated three probes with bevel angles 35, 40, and 45 degrees for their ... ...

    Abstract We report the development and evaluation of a simple compact probe that incorporates multiple beveled fibers for depth sensitive detection of spectroscopic signals in vivo. We evaluated three probes with bevel angles 35, 40, and 45 degrees for their collection efficiency and depth resolution using a thin highly scattering white substrate and found that a 40 degree bevel provides the best characteristics for depth-resolved spectroscopy. The depth sensitivity of the probe with 40 degree beveled fibers was then evaluated using multilayer phantoms with scattering properties mimicking precancerous tissue and in vivo on normal human oral mucosa. The results demonstrate that the use of multiple beveled fibers has the capability to simultaneously collect scattering spectra from a range of depths within epithelial tissue that has the potential to provide further significant improvement of detection and monitorin of epithelial precancers.
    MeSH term(s) Biomarkers, Tumor/analysis ; Epithelium/chemistry ; Equipment Design ; Equipment Failure Analysis ; Humans ; Miniaturization ; Mouth Neoplasms/chemistry ; Mouth Neoplasms/diagnosis ; Phantoms, Imaging ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrum Analysis/instrumentation ; Transducers
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2009-01-31
    Publishing country United States
    Document type Evaluation Studies ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1491859-6
    ISSN 1094-4087 ; 1094-4087
    ISSN (online) 1094-4087
    ISSN 1094-4087
    DOI 10.1364/oe.17.002780
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma.

    Wehrli, Marc / Guinn, Samantha / Birocchi, Filippo / Kuo, Adam / Sun, Yi / Larson, Rebecca C / Almazan, Antonio J / Scarfò, Irene / Bouffard, Amanda A / Bailey, Stefanie R / Anekal, Praju Vikas / Montero Llopis, Paula / Nieman, Linda T / Song, Yuhui / Xu, Katherine H / Berger, Trisha R / Kann, Michael C / Leick, Mark B / Silva, Harrison /
    Salas-Benito, Diego / Kienka, Tamina / Grauwet, Korneel / Armstrong, Todd D / Zhang, Rui / Zhu, Qingfeng / Fu, Juan / Schmidts, Andrea / Korell, Felix / Jan, Max / Choi, Bryan D / Liss, Andrew S / Boland, Genevieve M / Ting, David T / Burkhart, Richard A / Jenkins, Russell W / Zheng, Lei / Jaffee, Elizabeth M / Zimmerman, Jacquelyn W / Maus, Marcela V

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2024  Volume 30, Issue 9, Page(s) 1859–1877

    Abstract: Purpose: Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by ...

    Abstract Purpose: Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells).
    Experimental design: Using a suite of in vitro, in vivo, and ex vivo patient-derived models containing cancer cells and CAF, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAF within the TME. We developed and used patient-derived ex vivo models, including patient-derived organoids with patient-matched CAF and patient-derived organotypic tumor spheroids.
    Results: We demonstrated specific and significant binding of the TEAM to its respective antigens (CD3 and FAP) when released from mesothelin-targeting CAR T cells, leading to T-cell activation and cytotoxicity of the target cell. MesoFAP CAR-TEAM cells were superior in eliminating PDAC and CAF compared with T cells engineered to target either antigen alone in our ex vivo patient-derived models and in mouse models of PDAC with primary or metastatic liver tumors.
    Conclusions: CAR-TEAM cells enable modification of tumor stroma, leading to increased elimination of PDAC tumors. This approach represents a promising treatment option for pancreatic cancer.
    MeSH term(s) Humans ; Mesothelin ; Animals ; Mice ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/therapy ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/metabolism ; Tumor Microenvironment/immunology ; Immunotherapy, Adoptive/methods ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; CD3 Complex/immunology ; CD3 Complex/metabolism ; GPI-Linked Proteins/immunology ; GPI-Linked Proteins/metabolism ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Carcinoma, Pancreatic Ductal/immunology ; Carcinoma, Pancreatic Ductal/therapy ; Carcinoma, Pancreatic Ductal/pathology ; Carcinoma, Pancreatic Ductal/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Cancer-Associated Fibroblasts/metabolism ; Cancer-Associated Fibroblasts/immunology ; Membrane Proteins/immunology ; Membrane Proteins/metabolism ; Serine Endopeptidases/immunology ; Serine Endopeptidases/metabolism ; Adenocarcinoma/immunology ; Adenocarcinoma/therapy ; Adenocarcinoma/pathology ; Endopeptidases
    Chemical Substances Mesothelin (J27WDC343N) ; Receptors, Chimeric Antigen ; CD3 Complex ; GPI-Linked Proteins ; fibroblast activation protein alpha (EC 3.4.21.-) ; Membrane Proteins ; Serine Endopeptidases (EC 3.4.21.-) ; Endopeptidases (EC 3.4.-)
    Language English
    Publishing date 2024-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-23-3841
    Database MEDical Literature Analysis and Retrieval System OnLINE

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