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

Cancer Cell. 2023 Nov 13;41(11):1911-1926.e8. doi: 10.1016/j.ccell.2023.09.001. Epub 2023 Oct 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Stem Neoplasms* / drug therapy
  • Brain Stem Neoplasms* / pathology
  • Child
  • Diffuse Intrinsic Pontine Glioma*
  • Glioma* / pathology
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immunologic Memory
  • Tumor Microenvironment

Substances

  • Hepatitis A Virus Cellular Receptor 2