Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Alexandra Garancher1, Hiromichi Suzuki2, Svasti Haricharan3, Lianne Q Chau1, Meher Beigi Masihi1, Jessica M Rusert1, Paula S Norris3, Florent Carrette3, Megan M Romero4, Sorana A Morrissy2,5, Patryk Skowron2, Florence M G Cavalli2, Hamza Farooq2, Vijay Ramaswamy6, Steven J M Jones7, Richard A Moore7, Andrew J Mungall7, Yussanne Ma7, Nina Thiessen7, Yisu Li7, Alaide Morcavallo8, Lin Qi9,10, Mari Kogiso9, Yuchen Du9,10, Patricia Baxter9, Jacob J Henderson11, John R Crawford12, Michael L Levy13, James M Olson14, Yoon-Jae Cho11, Aniruddha J Deshpande1, Xiao-Nan Li9,10, Louis Chesler8, Marco A Marra7, Harald Wajant15, Oren J Becher4, Linda M Bradley3, Carl F Ware3, Michael D Taylor2, Robert J Wechsler-Reya16

  1. Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  2. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
  3. Tumor Microenvironment and Cancer Immunology Program, NCI-Designated Cancer Center and the Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  4. Department of Pediatrics, Northwestern University, Chicago, IL, USA.
  5. Dept. of Biochemistry and Molecular Biology, Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
  6. Division of Haematology/Oncology and Department of Paediatrics, Hospital for Sick Children, Toronto, Canada.
  7. Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.
  8. Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
  9. Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  10. Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University, Chicago, IL, USA.
  11. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
  12. Departments of Pediatrics and Neurosciences, University of California, San Diego - Rady Children's Hospital, San Diego, CA, USA.
  13. Department of Neurosurgery, University of California San Diego - Rady Children's Hospital, San Diego, CA, USA.
  14. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  15. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
  16. Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. rwreya@sbpdiscovery.org.

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.

Presented By Alexandra Garancher

Cancer Biology, Immunology & MicrobiologyNicholas Liao2020-07 (Jul)