한빛사논문
- 조회432
Il-Kyu Kim1,2,12, Mark S. Diamond1,2,12, Salina Yuan1,2,12, Samantha B. Kemp1,2, Benjamin M. Kahn1,2,3, Qinglan Li4,5, Jeffrey H. Lin1,2, Jinyang Li1,2, Robert J. Norgard1,2, Stacy K. Thomas1,2, Maria Merolle1,2, Takeshi Katsuda1,2, John W. Tobias6, Timour Baslan7, Katerina Politi8,9,10, Robert H. Vonderheide1,2,11 & Ben Z. Stanger1,2,3
1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6Penn Genomic Analysis Core, University of Pennsylvania, Philadelphia, PA, USA.
7Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
9Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
10Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
11Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA.
12These authors contributed equally: Il-Kyu Kim, Mark S. Diamond, Salina Yuan.
Corresponding authors : Correspondence to Robert H. Vonderheide or Ben Z. Stanger.
Abstract
Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-03-04)
- 국외 연구진
- 의약학 > 종양의학
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