Immunogenicity and Therapeutic Challenges of IDH-Mutant Gliomas

Background

Glioma is a common central nervous system tumor, and its treatment and prognosis vary significantly depending on molecular characteristics. In recent years, the diagnostic and prognostic significance of isocitrate dehydrogenase (IDH) mutations in gliomas has been increasingly recognized. IDH-mutant gliomas generally have a better prognosis but exhibit lower immunogenicity, leading to poor responses to immune checkpoint inhibitors (ICBs). The emergence of primary mismatch repair-deficient IDH-mutant astrocytoma (PMMRDIA) further exacerbates this therapeutic challenge. PMMRDIA is inherently resistant to the standard chemotherapeutic agent temozolomide (TMZ) and also shows resistance to ICBs. Therefore, understanding how IDH mutations affect the immunogenicity of gliomas and exploring potential therapeutic strategies have become a focus of current research.

Source of the Paper

This systematic review was authored by Olfat Ahmad, Tahani Ahmad, and Stefan M. Pfister, affiliated with the Hopp Children’s Cancer Center in Heidelberg, Germany; the German Cancer Research Center (DKFZ); the University of Oxford, UK; the King Hussein Cancer Center (KHCC) in Amman, Jordan; the IWK Health Center in Halifax, Canada; and Heidelberg University Hospital in Germany. The paper was published online on February 9, 2024, in the journal Molecular Oncology (DOI: 10.¹⁰⁰²⁄₁₈₇₈-0261.13598).

Main Content of the Paper

1. Immune Suppression Mechanisms in IDH-Mutant Gliomas

The immune suppression mechanisms in IDH-mutant gliomas primarily involve three aspects: epigenetic, metabolic, and paracrine effects. IDH mutations lead to the intracellular accumulation of R-2-hydroxyglutarate (R-2-HG), which inhibits multiple α-ketoglutarate-dependent hydroxylases, affecting DNA and histone methylation and resulting in the glioma-associated CpG island methylator phenotype (G-CIMP). This epigenetic reprogramming not only affects gene expression in tumor cells but also influences the function of immune cells in the tumor microenvironment (TME) through paracrine effects.

2. Impact of IDH Mutations on Immune Cells

2.1 Suppression of Antigen Presentation

In IDH-mutant gliomas, the expression of major histocompatibility complex (MHC) molecules is significantly reduced, leading to impaired antigen presentation by tumor cells. Additionally, IDH-mutant gliomas exhibit lower tumor mutational burden (TMB), further diminishing their immunogenicity.

2.2 Inhibition of Immune Cell Chemotaxis

In IDH-mutant gliomas, the expression of various chemokines is downregulated, resulting in reduced chemotaxis of immune cells to the TME. For example, downregulation of STAT1 leads to decreased expression of CXCL10, thereby inhibiting the chemotaxis of CD8+ T cells.

2.3 Functional Inhibition of Immune Cells

R-2-HG enters T cells and dendritic cells (DCs) through the sodium-dependent SLC13A3 transporter, inhibiting their functions. For instance, R-2-HG suppresses T cell proliferation and cytokine secretion and inhibits IL-12 production by DCs, thereby weakening T cell activation and anti-tumor immune responses.

3. Regulation of Immune Checkpoints by IDH Mutations

In IDH-mutant gliomas, the expression of multiple immune checkpoints, including PD-L1, PD-L2, and CTLA-4, is downregulated. This downregulation is primarily attributed to hypermethylation of the promoters of these genes. Specifically, the downregulation of PD-L1 directly contributes to the resistance of IDH-mutant gliomas to ICBs.

4. Diagnostic and Therapeutic Challenges of PMMRDIA

PMMRDIA, a newly defined subtype of IDH-mutant glioma, presents unique molecular characteristics and therapeutic challenges. PMMRDIA is inherently resistant to TMZ and also exhibits resistance to ICBs. Therefore, exploring targeted therapeutic strategies against IDH mutations and DNA methylation has become crucial for addressing the treatment challenges of PMMRDIA.

Significance and Value of the Paper

This systematic review comprehensively summarizes the immune suppression mechanisms in IDH-mutant gliomas and proposes targeted therapeutic strategies against IDH mutations and DNA methylation. In particular, the authors highlight the potential of combining IDH inhibitors and/or methylation inhibitors with ICBs, offering new insights for the treatment of PMMRDIA. Additionally, the review provides important directions for future research, such as further exploring the effects of R-2-HG on NK cells and tumor-associated macrophages (TAMs), as well as developing new IDH-targeted therapies.

Highlights

1. Comprehensive Summary of Immune Suppression Mechanisms in IDH-Mutant Gliomas: Detailed exploration of how IDH mutations affect glioma immunogenicity through epigenetic, metabolic, and paracrine effects.
2. Proposal of New Therapeutic Strategies: Emphasis on the potential of combining IDH inhibitors and/or methylation inhibitors with ICBs, offering new approaches for treating PMMRDIA.
3. Directions for Future Research: Identification of key areas for further investigation, including the effects of R-2-HG on NK cells and TAMs, and the development of novel IDH-targeted therapies.

Conclusion

This systematic review not only delves into the immune suppression mechanisms of IDH-mutant gliomas but also provides new insights for addressing the therapeutic challenges of PMMRDIA. By combining IDH inhibitors and/or methylation inhibitors with ICBs, it may be possible to enhance the response of IDH-mutant gliomas to immunotherapy, offering better treatment outcomes for patients.