Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

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

doi:10.1038/s41593-020-0628-4

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

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 LiAlaide 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

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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.

Original language	English (US)
Pages (from-to)	842-853
Number of pages	12
Journal	Nature Neuroscience
Volume	23
Issue number	7
DOIs	https://doi.org/10.1038/s41593-020-0628-4
State	Published - Jul 1 2020

ASJC Scopus subject areas

General Neuroscience

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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., ... Wechsler-Reya, R. J. (2020). Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Nature Neuroscience, 23(7), 842-853. https://doi.org/10.1038/s41593-020-0628-4

Garancher, A, Suzuki, H, Haricharan, S, Chau, LQ, Masihi, MB, Rusert, JM, Norris, PS, Carrette, F, Romero, MM, Morrissy, SA, Skowron, P, Cavalli, FMG, Farooq, H, Ramaswamy, V, Jones, SJM, Moore, RA, Mungall, AJ, Ma, Y, Thiessen, N, Li, Y, Morcavallo, A, Qi, L, Kogiso, M, Du, Y, Baxter, P, Henderson, JJ, Crawford, JR, Levy, ML, Olson, JM, Cho, YJ, Deshpande, AJ, Li, XN, Chesler, L, Marra, MA, Wajant, H, Becher, OJ, Bradley, LM, Ware, CF, Taylor, MD & Wechsler-Reya, RJ 2020, 'Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma', Nature Neuroscience, vol. 23, no. 7, pp. 842-853. https://doi.org/10.1038/s41593-020-0628-4

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title = "Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma",

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.",

author = "Alexandra Garancher and Hiromichi Suzuki and Svasti Haricharan and Chau, {Lianne Q.} and Masihi, {Meher Beigi} and Rusert, {Jessica M.} and Norris, {Paula S.} and Florent Carrette and Romero, {Megan M.} and Morrissy, {Sorana A.} and Patryk Skowron and Cavalli, {Florence M.G.} and Hamza Farooq and Vijay Ramaswamy and Jones, {Steven J.M.} and Moore, {Richard A.} and Mungall, {Andrew J.} and Yussanne Ma and Nina Thiessen and Yisu Li and Alaide Morcavallo and Lin Qi and Mari Kogiso and Yuchen Du and Patricia Baxter and Henderson, {Jacob J.} and Crawford, {John R.} and Levy, {Michael L.} and Olson, {James M.} and Cho, {Yoon Jae} and Deshpande, {Aniruddha J.} and Li, {Xiao Nan} and Louis Chesler and Marra, {Marco A.} and Harald Wajant and Becher, {Oren J.} and Bradley, {Linda M.} and Ware, {Carl F.} and Taylor, {Michael D.} and Wechsler-Reya, {Robert J.}",

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AU - Garancher, Alexandra

AU - Suzuki, Hiromichi

AU - Haricharan, Svasti

AU - Chau, Lianne Q.

AU - Masihi, Meher Beigi

AU - Rusert, Jessica M.

AU - Norris, Paula S.

AU - Carrette, Florent

AU - Romero, Megan M.

AU - Morrissy, Sorana A.

AU - Skowron, Patryk

AU - Cavalli, Florence M.G.

AU - Farooq, Hamza

AU - Ramaswamy, Vijay

AU - Jones, Steven J.M.

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Ma, Yussanne

AU - Thiessen, Nina

AU - Li, Yisu

AU - Morcavallo, Alaide

AU - Qi, Lin

AU - Kogiso, Mari

AU - Du, Yuchen

AU - Baxter, Patricia

AU - Henderson, Jacob J.

AU - Crawford, John R.

AU - Levy, Michael L.

AU - Olson, James M.

AU - Cho, Yoon Jae

AU - Deshpande, Aniruddha J.

AU - Li, Xiao Nan

AU - Chesler, Louis

AU - Marra, Marco A.

AU - Wajant, Harald

AU - Becher, Oren J.

AU - Bradley, Linda M.

AU - Ware, Carl F.

AU - Taylor, Michael D.

AU - Wechsler-Reya, Robert J.

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N2 - 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.

AB - 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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JO - Nature Neuroscience

JF - Nature Neuroscience

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ER -

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

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