دورية أكاديمية
أعرض في EDS

Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy.

التفاصيل البيبلوغرافية
العنوان: Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy.
المؤلفون: Mortensen REJ; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark., Holmström MO; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark.; Department of Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark., Lisle TL; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark., Hasselby JP; Department of Pathology, Rigshospitalet, Copenhagen, Denmark., Willemoe GL; Department of Pathology, Rigshospitalet, Copenhagen, Denmark., Met Ö; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark., Marie Svane I; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark., Johansen J; Department of Oncology, Herlev Hospital, Herlev, Denmark., Nielsen DL; Department of Oncology, Herlev Hospital, Herlev, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Chen IM; Department of Oncology, Herlev Hospital, Herlev, Denmark., Andersen MH; National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, Herlev, Denmark Mads.Hald.Andersen@regionh.dk.; Department of Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Mar; Vol. 11 (3).
نوع المنشور: Clinical Trial, Phase II; Randomized Controlled Trial; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print 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: Cancer Vaccines*/therapeutic use , Immune Checkpoint Inhibitors*/therapeutic use , Immunity, Cellular* , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/radiotherapy , T-Lymphocytes*/immunology, Epitopes ; Leukocytes, Mononuclear ; Transforming Growth Factor beta ; Tumor Microenvironment ; Vaccines, Subunit ; Humans ; Pancreatic Neoplasms
مستخلص: Background: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC).
Methods: Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry.
Results: PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15.
Conclusion: A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.
Competing Interests: Competing interests: MHA has made an invention based on the use of TGF-β for vaccinations. The rights of the invention have been transferred to Copenhagen University Hospital Herlev, according to the Danish Law of Public Inventions at Public Research Institutions. The capital region has licensed the rights to the company IO Biotech ApS. The patent application was filed by IO Biotech ApS. MHA is founder, advisor and shareholder in IO Biotech. IMS is co-founder, advisor and shareholder in IO Biotech. The additional authors declare no competing financial interests.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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فهرسة مساهمة: Keywords: Antigens; Immunotherapy; T-Lymphocytes; Tumor Microenvironment; Vaccination
المشرفين على المادة: 0 (Cancer Vaccines)
0 (Epitopes)
0 (Immune Checkpoint Inhibitors)
0 (Transforming Growth Factor beta)
0 (Vaccines, Subunit)
تواريخ الأحداث: Date Created: 20230322 Date Completed: 20230324 Latest Revision: 20231213
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10040073
DOI: 10.1136/jitc-2022-006432
PMID: 36948507
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2022-006432