IMMU-03. TUMOR NECROSIS FACTOR OVERCOMES IMMUNE EVASION IN P53-MUTANT MEDULLOBLASTOMA. (23rd April 2019)

• Record Type: Journal Article
• Authors: Garancher, Alexandra; Suzuki, Hiromichi; Haricharan, Svasti; Masihi, Meher Beigi; Rusert, Jessica M; Norris, Paula S; Carrette, Florent; Romero, Megan M; Morrissy, Sorana A; Skowron, Patryk; M.G. Cavalli, Florence; Farooq, Hamza; Ramaswamy, Vijay; J.M. Jones, Steven; Moore, Richard A; Mungall, Andrew J; Ma, Yussanne; Thiessen, Nina; Li, Yisu; Morcavallo, Alaide; Qi, Lin; Henderson, Jacob J; Crawford, John R; Levy, Michael L; Olson, James M; Cho, Yoon-Jae; Deshpande, Ani; Li, Xiao-Nan; Chesler, Louis; Marra, Marco A; Becher, Oren J; Bradley, Linda M; Ware, Carl F; Taylor, Michael D; Wechsler-Reya, Robert J;
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii93
• Page End: ii93
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.124
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Many immunotherapies act by enhancing the ability of T cells to kill tumor cells. But T cell killing depends on recognition of antigens presented by Class I MHC (MHC-I) on the tumor cell surface; if a tumor lacks MHC-I, it cannot be recognized by T cells. To study the efficacy of immunotherapy for Group 3 medulloblastoma, we have used mouse models driven by overexpression of M yc and dominant negative p 53 ("MP tumors"), or by overexpression of M yc and G fi1 ("MG tumors"). While MP tumors grow in immunocompetent mice, MG tumors don't grow, due to T-cell rejection. To understand this difference, we analyzed expression of immunoregulatory molecules, and found that MP tumors completely lack surface MHC-I. Mechanistically, this is because two key proteins required for MHC-I trafficking – TAP1 and ERAP1 – are targets of p53; since MP tumors lack functional p53, they also lack TAP1 and ERAP1, and surface MHC-I. These studies suggest that p53 plays a critical role in determining immunogenicity, and that p53-mutant tumors are resistant to immune attack. To overcome this resistance, we treated tumor cells with agents that regulate MHC-1. We found that low doses of tumor necrosis factor alpha (TNF) can rescue expression of ERAP, TAP and MHC-I on MP tumor cells. In vivo, TNF prolongs survival of tumor-bearing mice, and markedly augments the efficacy of immune checkpoint inhibitors. These results raise the possibility that TNF could be used prior to immunotherapy to render tumors more sensitive to T cell attack.