Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Journal: 
Nat Neurosci
Publication Year: 
2020
Authors: 
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 Li
Alaide 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
PubMed link: 
32424282
Public Summary: 
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-beta 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.
Scientific 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-beta 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.