Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis

ABSTRACT

Introduction

Gliomas are stratified by the presence of a hotspot mutation in the enzyme isocitrate dehydrogenase genes (IDH1/2). While mutated IDH (mIDH) correlates with better prognosis, the role of this mutation in antitumor immunity and the response to immunotherapy is not completely understood. Understanding the relationship between the genetic features of these tumors and the tumor immune microenvironment (TIME) may help to develop appropriate therapeutic strategies.

Areas covered

In this review we discussed the available literature related to the potential role of IDH mutations as an immunotherapeutic target in gliomas and profiled the immune transcriptome of glioma biopsies. We aimed to shed light on the role of mIDH on the immunological landscape of the different subtypes of gliomas, taking into account the most recent WHO classification of tumors of the central nervous system (CNS). We also discussed different immunotherapeutic approaches to target mIDH tumors and to overcome their immunosuppressive microenvironment.

Expert opinion

Data presented here indicates that the TIME not only differs in association with IDH mutation status, but also within glioma subtypes, suggesting that the cellular context affects the overall effect of this genetic lesion. Thus, specific therapeutic combinations may help patients diagnosed with different glioma subtypes.

KEYWORDS:

• GLIOMA
• IDH
• immunological checkpoints
• immunotherapy

Article highlights

• Diffuse gliomas with mIDH exhibit a cold immune phenotype.

• Contrary to other solid tumors, high levels of TILs in diffuse gliomas are associated with wtIDH expression and worse prognosis.

• The impact of IDH mutational status on the behavior of these tumors seems to be dependent on molecular changes related to additional genetic lesions that characterize each tumor subtype, as profound differences are observed between them. Thus, different therapeutic strategies may be required for each of these tumor subtypes.

• Although the inhibition of mIDH may boost the response to immunotherapeutic strategies, approaches that target downstream mediators, i.e. proinflammatory chemokines, or improved antitumor immunotherapies, i.e. anti-mIDH vaccines, may reverse the cold phenotype of these tumors without affecting the direct antitumoral effects of 2-hydroxyglutarate (2-HG) on glioma cells.

• Immunization against mIDH constitutes a promising therapeutic strategy to promote specific immunity against these tumors.

• Effective anti-glioma immunotherapy requires the combination of specific immunotherapeutic approaches and optimization of standard of care. In this way, they may trigger powerful immune responses that eliminate the tumor fast and resolve rapidly, without evolving into pro-tumorigenic chronic inflammation.

This box summarizes key points contained in the article.

Disclosure statement

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by Consejo Nacional de Investigaciones Científicas y Tecnológicas (Fellowships to A.J.N.C., J.A.P.A. and A.S.A); Instituto Nacional del Cáncer (Asistencia Financiera a Proyectos de Investigación en Cáncer IV to M.C.), Agencia Nacional de Promoción Científica y Tecnológica [PICT-2018-3088] and [PICT-2019-00117] to M.C.; Fellowship to N.G), and Consejo Interuniversitario Nacional (Fellowship to M.G.F.).