Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

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 su...

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Bibliographic Details
Published in:Nature neuroscience 2020-07, Vol.23 (7), p.842-853
Main Authors: Garancher, Alexandra, Suzuki, Hiromichi, Haricharan, Svasti, Chau, Lianne Q, Masihi, Meher Beigi, Rusert, Jessica M, Norris, Paula S, Carrette, Florent, Romero, Megan M, Morrissy, Sorana A, Skowron, Patryk, Cavalli, Florence M G, Farooq, Hamza, Ramaswamy, Vijay, Jones, Steven J M, Moore, Richard A, Mungall, Andrew J, Ma, Yussanne, Thiessen, Nina, Li, Yisu, Morcavallo, Alaide, Qi, Lin, Kogiso, Mari, Du, Yuchen, Baxter, Patricia, Henderson, Jacob J, Crawford, John R, Levy, Michael L, Olson, James M, Cho, Yoon-Jae, Deshpande, Aniruddha J, Li, Xiao-Nan, Chesler, Louis, Marra, Marco A, Wajant, Harald, Becher, Oren J, Bradley, Linda M, Ware, Carl F, Taylor, Michael D, Wechsler-Reya, Robert J
Format: Article
Language:English
Subjects:
Aminopeptidase
Animals
Antigens
Care and treatment
Cell recognition
Cell surface
Cerebellar Neoplasms - genetics
Cerebellar Neoplasms - immunology
Cerebellar Neoplasms - metabolism
Cytotoxicity
Genetic aspects
Immune checkpoint inhibitors
Immune evasion
Immunotherapy
Inhibitors
Lymphocytes
Lymphocytes T
Lymphotoxin
Major histocompatibility complex
Medulloblastoma
Medulloblastoma - genetics
Medulloblastoma - immunology
Medulloblastoma - metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Mutants
Necrosis
Neoplasm Transplantation
p53 Protein
Peptide transporter
Physiological aspects
Prognosis
Rejection
Sensitivity enhancement
Synergism
T cells
Testing
Tumor cells
Tumor Escape - immunology
Tumor necrosis factor
Tumor Necrosis Factor-alpha - immunology
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-TNF
Tumor suppressor genes
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - immunology
Tumor Suppressor Protein p53 - metabolism
Tumors
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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-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.
ISSN:1097-6256
1546-1726
DOI:10.1038/s41593-020-0628-4