Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Lianne Q. Chau, Meher Beigi Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Steven J.M. Jones, Richard A. Moore, Andrew J. Mungall, Yussanne Ma, Nina Thiessen, Yisu LiAlaide Morcavallo, Lin Qi, Mari Kogiso, Yuchen Du, Patricia Baxter, Jacob J. Henderson, John R. Crawford, Michael L. Levy, James M. Olson, Yoon Jae Cho, Aniruddha J. Deshpande, Xiao Nan Li, Louis Chesler, Marco A. Marra, Harald Wajant, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)842-853
Number of pages12
JournalNature neuroscience
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2020

ASJC Scopus subject areas

  • Neuroscience(all)

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