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

Autor:	Ausejo-Mauleon I; 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., Labiano S; 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., de la Nava D; 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., Laspidea V; 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., Zalacain M; 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., Marrodán L; 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., García-Moure M; 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., González-Huarriz M; 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., Hervás-Corpión I; 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., Dhandapani L; 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., Vicent S; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain., Collantes M; Radiopharmacy Unit, Clínica Universidad de Navarra, Pamplona, Spain; Translational Molecular Imaging Unit, Clínica Universidad de Navarra, Pamplona, Spain., Peñuelas I; 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., Becher OJ; Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, NY, USA., Filbin MG; 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., Jiang L; 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., Labelle J; 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., de Biagi-Junior CAO; 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., Nazarian J; 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., Laternser S; Division of Oncology and Children's Research Center, DIPG/DMG Research Center Zurich, University Children's Hospital Zurich, Zurich, Switzerland., Phoenix TN; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA., van der Lugt J; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands., Kranendonk M; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands., Hoogendijk R; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands., Mueller S; University of California, San Francisco, San Francisco, CA, USA., De Andrea C; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain., Anderson AC; 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., Guruceaga E; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Bioinformatics Platform, CIMA-Universidad de Navarra, Pamplona, Spain., Koschmann C; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Yadav VN; 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., Gállego Pérez-Larraya J; 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., Patiño-García A; 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., Pastor F; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Molecular Therapeutics Program, CIMA-Universidad de Navarra, Pamplona, Spain., Alonso MM; 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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2023 Nov 13; Vol. 41 (11), pp. 1911-1926.e8. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1016/j.ccell.2023.09.001
Abstrakt:	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. Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Excepgen, which have interests in cancer immunotherapy. A.C.A. is a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital. The rest of authors do not have potential conflicts of interest to disclose. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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