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.
Health Research Institute of Navarra (IdiSNA), Pamplona, Spain; Solid Tumor Program, CIMA-Universidad de Navarra, Pamplona, Spain.
Cancer Cell. 2023 Nov 13;41(11):1911-1926.e8. doi: 10.1016/j.ccell.2023.09.001. Epub 2023 Oct 5.
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.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种侵袭性脑干肿瘤，也是导致儿童癌症相关死亡的主要原因。迄今为止，这些肿瘤仍然无法治愈，这凸显了开发有效治疗方法的必要性。在这项研究中，我们证明了免疫检查点 TIM-3（HAVCR2）在 DIPG 中的肿瘤细胞和微环境细胞（主要是小胶质细胞和巨噬细胞）中均高度表达。我们发现，在 DIPG 的同基因模型中抑制 TIM-3 可延长生存期并产生无疾病的长期存活者，这些存活者具有免疫记忆。这种抗肿瘤作用是由 TIM-3 抑制在肿瘤细胞中的直接作用、几种免疫细胞群的协调作用以及趋化因子/细胞因子的分泌所驱动的，这些趋化因子/细胞因子可创造有利于强效抗肿瘤免疫反应的促炎肿瘤微环境。这项工作揭示了 TIM-3 是 DIPG 中的一个真正的靶点，并支持其临床转化。
