@article{b9691b0aaaa54ec998c1ef44d0ebf468,
title = "Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma",
abstract = "Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.",
author = "Alexandra Garancher and Hiromichi Suzuki and Svasti Haricharan and Chau, {Lianne Q.} and Masihi, {Meher Beigi} and Rusert, {Jessica M.} and Norris, {Paula S.} and Florent Carrette and Romero, {Megan M.} and Morrissy, {Sorana A.} and Patryk Skowron and Cavalli, {Florence M.G.} and Hamza Farooq and Vijay Ramaswamy and Jones, {Steven J.M.} and Moore, {Richard A.} and Mungall, {Andrew J.} and Yussanne Ma and Nina Thiessen and Yisu Li and Alaide Morcavallo and Lin Qi and Mari Kogiso and Yuchen Du and Patricia Baxter and Henderson, {Jacob J.} and Crawford, {John R.} and Levy, {Michael L.} and Olson, {James M.} and Cho, {Yoon Jae} and Deshpande, {Aniruddha J.} and Li, {Xiao Nan} and Louis Chesler and Marra, {Marco A.} and Harald Wajant and Becher, {Oren J.} and Bradley, {Linda M.} and Ware, {Carl F.} and Taylor, {Michael D.} and Wechsler-Reya, {Robert J.}",
note = "Funding Information: The authors gratefully acknowledge the Animal Facilities at UCSD and SBP for help with animal care and husbandry; S. Tacheva Grigorova for assistance generating conditional Ptch1 knockout mice; Y. Altman of the Flow Cytometry Shared Resource at SBP; and J. Olvera and C. Fine of the Stem Cell Core at UCSD for assistance with FACS sorting and analysis. We are also indebted to T. Milde at the Hopp Children{\textquoteright}s Cancer Center, Heidelberg, for providing HD-MB03 and BT-084 cells; to M. Monje at Stanford University for sharing human DIPG cell lines; and to J. Scott-Browne and A. Rao at the La Jolla Institute for Immunology for providing p53 shRNA constructs. We thank S. Baker and L. Hover at St. Jude Children{\textquoteright}s Research Hospital, L. Attardi at Stanford University, O. Ayrault and A. Forget at Institut Curie, and J. Rich, B. Prager and L. Kim from UCSD for help with analysis of gene and protein expression in p53-mutant and wild-type tumors. M.D.T. is supported by the National Institutes of Health (NIH) (R01CA148699 and R01CA159859), the Pediatric Brain Tumour Foundation, the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Cure Search Foundation, b.r.a.i.n. child, Meagan{\textquoteright}s Walk, the SWIFTY Foundation, the Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, the V Foundation for Cancer Research and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK Brain Tumour Award and a Stand Up To Cancer (SU2C) St. Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. This work was supported by funding from the National Cancer Institute (2R01 CA159859-06 and P30 CA30199 (to R.J.W.-R.)), P01 CA177322 (to C.F.W.), K22 CDA CA229613 (to S.H), NIH (R01 AI048073) (to C.F.W.), Forschungsgemeinschaft (DFG, German Research Foundation) (324392634–TRR221 and WA 1025/31-1) (to H.W.), the V Foundation, the Pediatric Brain Tumor Foundation, Accelerate Brain Cancer Cure, Alex{\textquoteright}s Lemonade Stand Foundation (to R.J.W.-R. and O.J.B.), William{\textquoteright}s Superhero Fund (to R.J.W.-R.), the McDowell Charity Trust (to R.J.W.-R.), Madox{\textquoteright}s Warriors (to O.J.B.), the Cristian Rivera Foundation (to O.J.B.), the Fly A Kite Foundation (to O.J.B.) and the California Institute for Regenerative Medicine (to R.J.W.-R.). This work is dedicated to the memory of William Schultz and Errol McDowell. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = jul,
day = "1",
doi = "10.1038/s41593-020-0628-4",
language = "English (US)",
volume = "23",
pages = "842--853",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "7",
}