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

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

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: mmalonso@unav.es.
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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