Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

• Published in: Nature neuroscience Vol. 23; no. 7; pp. 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: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2020
• 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; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-020-0628-4

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.