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Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Garancher, A.; Suzuki, H.; Haricharan, S.; Chau, L. Q.; Masihi, M. B.; Rusert, J. M.; Norris, P. S.; Carrette, F.; Romero, M. M.; Morrissy, S. A.; Skowron, P.; Cavalli, F. M. G.; Farooq, H.; Ramaswamy, V.; Jones, S. J. M.; Moore, R. A.; Mungall, A. J.; Ma, Y.; Thiessen, N.; Li, Y.; Morcavallo, A.; Qi, L.; Kogiso, M.; Du, Y.; Baxter, P.; Henderson, J. J.; Crawford, J. R.; Levy, M. L.; Olson, J. M.; Cho, Y. J.; Deshpande, A. J.; Li, X. N.; Chesler, L.; Marra, M. A.; Wajant, H.; Becher, O. J.; Bradley, L. M.; Ware, C. F.; Taylor, M. D.; Wechsler-Reya, R. J.

Nat Neurosci. 2020 May 20; 23(7):842-853

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.

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