Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Nat Neurosci. 2020 Jul;23(7):842-853. doi: 10.1038/s41593-020-0628-4. Epub 2020 May 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / immunology*
  • Cerebellar Neoplasms / metabolism
  • Medulloblastoma / genetics
  • Medulloblastoma / immunology*
  • Medulloblastoma / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Tumor Escape / immunology*
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / immunology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Trp53 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53