Abstract LB-333: IDH1 modulates the immune response to glioblastoma.

Abstract

Abstract Dendritic cell (DC) vaccines for glioblastoma (GBM) can effectively extend overall patient survival, but they are not curative. Younger patients responded poorly to vaccination in ours and other trials. Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in younger patients, encouraging the hypothesis that IDH1 mutation may subvert the clinical benefits of DC vaccination. Sequencing IDH1-mutated human GBM samples revealed an increase in IDH1 mutated tumor tissue after vaccination, consistent with this hypothesis. This led us to consider whether CTL recognition might be functionally altered by IDH1 and/or its mutation. Indeed, alloreactive CD8+ hybridoma cells exhibited significantly delayed lysis of GL26 cells expressing mutant IDH1 relative to untransfected GL26, but significantly increased lysis of GL26 transfected with unmutated IDH1. In contrast, wild-type and mutant IDH1 transfectants of GL26 exhibited identical sensitivity to imidazole-induced cell death, as well as identical MHC I expression. Moreover, preliminary studies suggest that wild-type and mutant IDH1 transfectants of GL26 are differentially sensitive to DC vaccination, with mutant IDH1 abrogating the longer survival conferred by such treatment. We therefore examined the possibility that these observed differences were mediated by a novel, immune-specific property of IDH1. Generalized sialidase activity can de-sialylate the CD8 coreceptor on T cells, and such modification enhances CD8 binding to MHC I, thereby modulating T cell responsiveness to MHC I-bound peptides. As the IDH1 catalytic site is structurally similar to microbial sialidase, we hypothesized that IDH1 possesses CD8-directed sialidase activity capable of enhancing CTL lysis, and that IDH1mutation critically diminishes this activity. Accordingly, IDH1 treatment increased binding to tumor pHLA multimers and to PNA lectin by human CD8 T cells, with the pHLA binding inhibited by either free sialic acid prior to treatment, or by anti-CD3 antibody after treatment. In addition, IDH1 treatment increased binding to several tumor pMHCI multimers by mouse CD8 T cells, and markedly increased IFN-γ production in response to stimulation by such multimers. Finally, labeled IDH1 bound to the surface of spleen cells, and physiologic concentrations of IDH1 specifically associated with a putative surface heterodimer resembling the CD8 coreceptor in murine T cell lysates. Together, these results suggest that wild-type IDH1possesses immune-specific sialidase function that enhances CTL lysis. In contrast, mutant IDH1 appears to delay immune lysis of tumor cells expressing it, and abrogates vaccine benefits, potentially by diminishing its immune-specific sialidase function. Citation Format: Ryan Cordner, Michelle Jhun, Akanksha Panwar, HongQiang Wang, Nicole Yeager, Joseph McAbee, Armen Mardiros, Akane Takei, Xuemo Fan, Emmaunel Jouanneau, Keith Black, Christopher Wheeler. IDH1 modulates the immune response to glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2013-LB-333