Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma
Pavlina Chuntova, Akane Yamamichi, Tiffany Chen, Rohini Narayanaswamy, Sébastien Ronseaux, Christine C. Hudson, Adriana E. Tron, Marc L. Hyer, Megan Montoya, Abigail Mende, Takahide Nejo, Kira Downey, David Diebold, Min Lu, Brandon Nicolay, Hideho Okada
Abstract
Background Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the ‘cold’ tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade. Methods An IDH1 R132H glioma model was created in syngeneic HLA-A2/HLA-DR1 -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1 R132H peptide vaccination or anti-PD-1 immune checkpoint blockade. Results The HLA-A2/HLA-DR1 -syngeneic IDH1 R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1 R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1 R132H gliomas in a CD4 + and CD8 + cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4 + tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1 R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 R132H and DR1-IDH1 R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone. Conclusion The development of effective IDH1 R132H -targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1 -syngeneic IDH1 R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.