دورية أكاديمية
أعرض في EDS

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.

التفاصيل البيبلوغرافية
العنوان: Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.
المؤلفون: Horvat NK; Department of Pediatric Hematology, Oncology and Immunology, Emory University, Atlanta, Georgia, USA., Karpovsky I; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Phillips M; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Wyatt MM; Department of Surgery, Department of Microbiology & Immunology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA., Hall MA; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Herting CJ; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Hammons J; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Mahdi Z; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA., Moffitt RA; Department of Hematology and Oncology, Emory University, Atlanta, Georgia, USA., Paulos CM; Department of Surgery, Department of Microbiology & Immunology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA gregory.b.lesinski@emory.edu chrystal.mary.paulos@emory.edu., Lesinski GB; Department of Hematology and Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA gregory.b.lesinski@emory.edu chrystal.mary.paulos@emory.edu.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Jan 08; Vol. 12 (1). Date of Electronic Publication: 2024 Jan 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: Pancreatic Neoplasms*/therapy , Carcinoma, Pancreatic Ductal*/therapy, Humans ; Animals ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins p21(ras) ; CD8-Positive T-Lymphocytes ; Tumor Suppressor Protein p53 ; Tumor Microenvironment
مستخلص: Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.
Methods: Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (Kras LSL-G12D/+ p53 -/- and Kras LSL-G12D/+ p53 LSL-R172H/+ , respectively).
Results: The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4 + and CD8 + T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors.
Conclusions: Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.
Competing Interests: Competing interests: GBL has consulted for ProDa Biotech and received compensation. GBL has also received research funding through a sponsored research agreement between Emory University and Merck and Co, Bristol-Myers Squibb, Boehringer Ingelheim, and Vaccinex. CP has received research funding through a sponsored research agreement between the Medical University of South Carolina and Obsidian, Lycera, and ThermoFisher, and is the cofounder of Ares Immunotherapy.
(© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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معلومات مُعتمدة: R01 CA208514 United States CA NCI NIH HHS; R01 CA175061 United States CA NCI NIH HHS; P30 CA138292 United States CA NCI NIH HHS; R50 CA233186 United States CA NCI NIH HHS; R01 CA275199 United States CA NCI NIH HHS; R01 CA228406 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: CD4-CD8 ratio; T-lymphocytes; receptors, chimeric antigen; receptors, immunologic; tumor microenvironment
المشرفين على المادة: EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
0 (Tumor Suppressor Protein p53)
تواريخ الأحداث: Date Created: 20240108 Date Completed: 20240110 Latest Revision: 20240315
رمز التحديث: 20240315
مُعرف محوري في PubMed: PMC10806555
DOI: 10.1136/jitc-2023-008086
PMID: 38191243
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2023-008086