TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory

  • Cancer Cell. 2023 Oct 3:S1535-6108(23)00318-5. doi: 10.1016/j.ccell.2023.09.001.
Iker Ausejo-Mauleon  1 ,  Sara Labiano  1 ,  Daniel de la Nava  1 ,  Virginia Laspidea  1 ,  Marta Zalacain  1 ,  Lucía Marrodán  1 ,  Marc García-Moure  1 ,  Marisol González-Huarriz  1 ,  Irati Hervás-Corpión  1 ,  Laasya Dhandapani  1 ,  Silvestre Vicent  2 ,  Maria Collantes  3 ,  Iván Peñuelas  4 ,  Oren J Becher  5 ,  Mariella G Filbin  6 ,  Li Jiang  6 ,  Jenna Labelle  6 ,  Carlos A O de Biagi-Junior  6 ,  Javad Nazarian  7 ,  Sandra Laternser  8 ,  Timothy N Phoenix  9 ,  Jasper van der Lugt  10 ,  Mariette Kranendonk  10 ,  Raoull Hoodendijk  10 ,  Sabine Mueller  11 ,  Carlos De Andrea  12 ,  Ana C Anderson  13 ,  Elizabeth Guruceaga  14 ,  Carl Koschmann  15 ,  Viveka Nand Yadak  16 ,  Jaime Gállego Pérez-Larraya  17 ,  Ana Patiño-García  1 ,  Fernando Pastor  18 ,  Marta M Alonso  19
Affiliations
  • 1. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.
  • 2. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain.
  • 3. Radiopharmacy Unit, Clínica Universidad de Navarra, Pamplona, Spain; Translational Molecular Imaging Unit, Clínica Universidad de Navarra, Pamplona, Spain.
  • 4. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Radiopharmacy Unit, Clínica Universidad de Navarra, Pamplona, Spain; Translational Molecular Imaging Unit, Clínica Universidad de Navarra, Pamplona, Spain.
  • 5. Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, NY, USA.
  • 6. Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 7. Children's National Health System, Center for Genetic Medicine Research, Washington, DC, USA; Virginia Tech University, Washington, DC, USA; Division of Oncology and Children's Research Center, DIPG/DMG Research Center Zurich, University Children's Hospital Zurich, Zurich, Switzerland.
  • 8. Division of Oncology and Children's Research Center, DIPG/DMG Research Center Zurich, University Children's Hospital Zurich, Zurich, Switzerland.
  • 9. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
  • 10. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 11. University of California, San Francisco, San Francisco, CA, USA.
  • 12. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 13. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 14. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Bioinformatics Platform, CIMA-Universidad de Navarra, Pamplona, Spain.
  • 15. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
  • 16. Department of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, KS, USA; Department of Pediatrics, Children's Mercy Research Institute (CMRI), Kansas City, KS, USA; Department of Cancer Biology, University of Kansas Cancer Center. Kansas City, KS, USA.
  • 17. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain; Department of Neurology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 18. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Molecular Therapeutics Program, CIMA-Universidad de Navarra, Pamplona, Spain.
  • 19. Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain. Electronic address: [email protected].
PMID: 37802053 DOI: 10.1016/j.ccell.2023.09.001
Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.

Keywords
DIPG; DMGs; TIM-3; diffuse midline glioma; immune checkpoint; immunotherapy; macrophages; microglia; pediatric brain tumor; tumor microenvironment.
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