TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory
Iker Ausejo‐Mauleon, Sara Labiano, Daniel de la Nava, Virginia Laspidea, Marta Zalacaín, Lucía Marrodán, Marc García-Moure, Marisol González-Huarriz, Irati Hervás-Corpión, Laasya Dhandapani, Silvestre Vicent, María Collantes, Iván Peñuelas, Oren J. Becher, Mariella G. Filbin, Li Jiang, Jenna LaBelle, Carlos A O de Biagi-Junior, Javad Nazarian, Sandra Laternser, Timothy N. Phoenix, Jasper van der Lugt, Mariëtte E.G. Kranendonk, Raoull Hoogendijk, Sabine Mueller, Carlos de Andrea, Ana C. Anderson, Elizabeth Guruceaga, Carl Koschmann, Viveka Nand Yadav, Jaime Gállego Pérez‐Larraya, Ana Patiño‐García, Fernando Pastor, Marta M. Alonso
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.