TIM-3 Blockade in Diffuse Intrinsic Pontine Glioma Models Promotes Tumor Regression and Antitumor Immune Memory

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.

Citing Articles

The Role of TIM-3 in Glioblastoma Progression.

Ahmady F, Sharma A, Achuthan A, Kannourakis G, Luwor R Cells. 2025; 14(5).

PMID: 40072074 PMC: 11899008. DOI: 10.3390/cells14050346.

Single-cell sequencing uncovers the mechanistic role of DAPK1 in glioma and its diagnostic and prognostic implications.

Yu T, Ding Y, Zhao S, Zhao J, Gu Y, Chen D Front Immunol. 2025; 15:1463747.

PMID: 39926603 PMC: 11802534. DOI: 10.3389/fimmu.2024.1463747.

ALKBH5 acts a tumor-suppressive biomarker and is associated with immunotherapy response in hepatocellular carcinoma.

Ma H, Hong Y, Xu Z, Weng Z, Yang Y, Jin D Sci Rep. 2025; 15(1):55.

PMID: 39747943 PMC: 11696456. DOI: 10.1038/s41598-024-84050-7.

Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8 T Cells during JEV Infection.

Zhang W, Yu Q, Gao X, Chen H, Su J, Chen Y Int J Biol Sci. 2024; 20(15):5959-5978.

PMID: 39664572 PMC: 11628328. DOI: 10.7150/ijbs.102372.

Relationship between EZH2 expression and prognosis of patients with hepatocellular carcinoma using a pathomics predictive model.

Zhou X, Man M, Cui M, Zhou X, Hu Y, Liu Q Heliyon. 2024; 10(20):e38562.

PMID: 39640777 PMC: 11619983. DOI: 10.1016/j.heliyon.2024.e38562.

References

Ndhlovu L, Lopez-Verges S, Barbour J, Jones R, Jha A, Long B . Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood. 2012; 119(16):3734-43. PMC: 3335380. DOI: 10.1182/blood-2011-11-392951. View

Kline C, Liu S, Duriseti S, Banerjee A, Nicolaides T, Raber S . Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience. J Neurooncol. 2018; 140(3):629-638. DOI: 10.1007/s11060-018-2991-5. View

Meel M, de Gooijer M, Metselaar D, Sewing A, Zwaan K, Waranecki P . Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma. Clin Cancer Res. 2020; 26(13):3319-3332. DOI: 10.1158/1078-0432.CCR-19-3538. View

Chen Z, Yu H, Li H, Shen H, Li X, Zhang J . Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats. CNS Neurosci Ther. 2019; 25(6):674-684. PMC: 6515709. DOI: 10.1111/cns.13100. View

Zhang H, Song Y, Yang H, Liu Z, Gao L, Liang X . Tumor cell-intrinsic Tim-3 promotes liver cancer via NF-κB/IL-6/STAT3 axis. Oncogene. 2018; 37(18):2456-2468. DOI: 10.1038/s41388-018-0140-4. View

Hoffman L, Veldhuijzen van Zanten S, Colditz N, Baugh J, Chaney B, Hoffmann M . Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol. 2018; 36(19):1963-1972. PMC: 6075859. DOI: 10.1200/JCO.2017.75.9308. View

van Hooren L, Vaccaro A, Ramachandran M, Vazaios K, Libard S, van de Walle T . Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat Commun. 2021; 12(1):4127. PMC: 8257767. DOI: 10.1038/s41467-021-24347-7. View

Jurga A, Paleczna M, Kuter K . Overview of General and Discriminating Markers of Differential Microglia Phenotypes. Front Cell Neurosci. 2020; 14:198. PMC: 7424058. DOI: 10.3389/fncel.2020.00198. View

Miklja Z, Yadav V, Cartaxo R, Siada R, Thomas C, Cummings J . Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma. J Clin Invest. 2020; 130(10):5313-5325. PMC: 7524471. DOI: 10.1172/JCI133310. View

10.

Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary S . Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017; 19(9):1279-1280. PMC: 5570207. DOI: 10.1093/neuonc/nox107. View

11.

Warren K . Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma. Front Oncol. 2018; 8:239. PMC: 6037693. DOI: 10.3389/fonc.2018.00239. View

12.

de Groot J, Penas-Prado M, Alfaro-Munoz K, Hunter K, Pei B, OBrien B . Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. Neuro Oncol. 2019; 22(4):539-549. PMC: 7158647. DOI: 10.1093/neuonc/noz185. View

13.

So E, Khaladj-Ghom A, Ji Y, Amin J, Song Y, Burch E . NK cell expression of Tim-3: First impressions matter. Immunobiology. 2019; 224(3):362-370. DOI: 10.1016/j.imbio.2019.03.001. View

14.

Panditharatna E, Yaeger K, Kilburn L, Packer R, Nazarian J . Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape. Cancer Genet. 2015; 208(7-8):367-73. DOI: 10.1016/j.cancergen.2015.04.008. View

15.

Heiss J, Jamshidi A, Shah S, Martin S, Wolters P, Argersinger D . Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma. J Neurosurg Pediatr. 2018; 23(3):333-342. PMC: 7266009. DOI: 10.3171/2018.9.PEDS17225. View

16.

Szychot E, Walker D, Collins P, Hyare H, Shankar A, Bienemann A . Clinical experience of convection-enhanced delivery (CED) of carboplatin and sodium valproate into the pons for the treatment of diffuse intrinsic pontine glioma (DIPG) in children and young adults after radiotherapy. Int J Clin Oncol. 2021; 26(4):647-658. DOI: 10.1007/s10147-020-01853-0. View

17.

Laspidea V, Puigdelloses M, Labiano S, Marrodan L, Garcia-Moure M, Zalacain M . Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas. JCI Insight. 2022; 7(7). PMC: 9057625. DOI: 10.1172/jci.insight.154812. View

18.

Liu J, Wu L, Yang L, Deng W, Mao L, Wu H . Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. J Exp Clin Cancer Res. 2018; 37(1):44. PMC: 5838931. DOI: 10.1186/s13046-018-0713-7. View

19.

Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T . Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol. 2017; 20(5):674-686. PMC: 5892140. DOI: 10.1093/neuonc/nox208. View

20.

Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C . Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc Natl Acad Sci U S A. 2018; 115(17):E4041-E4050. PMC: 5924916. DOI: 10.1073/pnas.1720948115. View