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Published on: November 28, 2015
Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment
Abstract:
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor. They show that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutated forms of isocitrate dehydrogenase (IDH1 and IDH2), reduces the expression of STAT1, thereby limiting the production of the chemokines CXCL9 and CXCL10. As a result, IDH1-mutated tumors are less effectively infiltrated by CD8+ T cells, contributing to tumor escape. Finally, in mice harboring syngeneic gliomas, an inhibitor of 2HG synthesis complemented vaccination to ameliorate tumor control. Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy.
Insights
Malignant gliomas evade immune attack by producing 2-hydroxyglutarate (2HG), which blocks CD8+ T cell migration. Inhibiting 2HG synthesis may improve immunotherapy by enhancing T cell infiltration for better tumor control.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immunotherapy shows promise for aggressive cancers like melanoma and lung cancer.
- Malignant gliomas are being investigated for immunotherapy, but their immune evasion mechanisms require further study.
- Impaired CD8+ T cell recruitment hinders glioma containment and elimination.
Purpose of the Study:
- To investigate how gliomas evade immune surveillance.
- To understand the role of specific mutations in glioma immune evasion.
- To identify strategies for enhancing antitumor immune responses in gliomas.
Main Methods:
- Analysis of gliomas exploiting enzymatic activity from common mutations.
- Investigating the effect of 2-hydroxyglutarate (2HG), produced by mutated isocitrate dehydrogenase (IDH1 and IDH2), on immune cell migration.
- Assessing the impact of reduced STAT1 and chemokine (CXCL9, CXCL10) expression on CD8+ T cell infiltration.
- Evaluating the efficacy of a 2HG synthesis inhibitor combined with vaccination in a mouse glioma model.
Main Results:
- Gliomas with mutations in isocitrate dehydrogenase (IDH1/IDH2) produce 2-hydroxyglutarate (2HG).
- 2HG reduces STAT1 expression, leading to decreased CXCL9 and CXCL10 chemokine production.
- This reduction impairs CD8+ T cell migration to IDH1-mutated gliomas, contributing to immune escape.
- Inhibition of 2HG synthesis, combined with vaccination, improved tumor control in mice.
Conclusions:
- IDH1-mutated gliomas utilize 2HG to suppress immune surveillance by limiting CD8+ T cell infiltration.
- Targeting 2HG production offers a potential strategy to enhance immunotherapy efficacy for gliomas.
- Increasing immune cell infiltration is crucial for achieving successful immunotherapy against gliomas.
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