Dear All,

I would like to cordially invite you to the Nencki Institute Seminar which will take place on the 29th of February at 3pm in the CN lecture Hall.. We will host Prof. Maria Castro from the Department of Neurosurgery, Department of Cell and Developmental Biology, Rogel Cancer Center, Immunology Graduate Program, Cancer Biology Graduate Program, University of Michigan Medical School.

Her talk will be entitled: Reprogramming the glioma immune microenvironment: mechanisms impacting immune mediated therapies.

Gliomas are highly infiltrative brain tumors accounting for 32% of all primary central nervous system malignancies. With advances in molecular biology and sequencing technologies, a distinct profile of genetic alterations for gliomas has emerged. A gain-of-function mutation in the gene encoding isocitrate dehydrogenase 1 (mIDH1) mutation has been reported in ~15.7% of all adult gliomas.  This mutation results in the replacement of arginine (R) for histidine (H) at amino acid residue 132 (R132H).  Patients harboring mIDH1 gliomas have significantly better prognosis (~6.6 years) than patients with wild type IDH1 (wt-IDH1) gliomas  (~1.6 years)   Less common IDH2 mutations occur in an analogous codon at position R172. Although IDH1/2 mutations are heterozygous, they exert a dominant gain of function enzymatic activity which leads to the production of 2-hydroxyglutarate (2HG). Excessive 2HG production causes DNA hypermethylation via inhibition of methylcytosine dioxygenase TET2, and also promotes histone hypermethylation through competitive inhibition of α-ketoglutarate (αKG)-dependent Jumonji-C histone demethylases. This leads to epigenetic reprogramming the transcriptome within mIDH1 glioma cells. Several studies suggested that mIDH1 may play a critical role in shaping the immunological landscape of the tumor immune microenvironment (TME). We show that mutant mIDH1 synthetizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ immune transcriptome leading to the reversion of the glioma immunosuppressive microenvironment. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells compartment infiltrating the TME. We uncovered that the immature myeloid cells-infiltrating the mIIDH1 TME are mainly non-suppressive neutrophils and pre-neutrophils. Myeloid cells’ reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem-like cells. Blocking G-CSF in mIDH1 glioma-bearing mice restores the inhibitory potential of myeloid cells, accelerating tumor progression. Also, we demonstrate that G-CSF reprograms bone-marrow granulopoiesis resulting in non-inhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy. In conclusion, out results uncover an important role of mIDH1 on reprogramming the phenotypic and functional diversity of myeloid cells in glioma TME, a feature that can be harnessed to enhance the efficacy of immunotherapies in glioma patients.
Our findings also demonstrate that treating mIDH1 glioma–bearing mice with IDH1-R132H inhibitor alone or in combination with ionizing radiation (IR) and temozolomide (TMZ), which is standard of care (SOC) for mIDH1 glioma patients, substantially prolonged the median survival (MS) of mIDH1 glioma–bearing mice and elicited antiglioma immunity. To date, the efficacy of PD-1/PD-L1 immune checkpoint blockade therapy has not been explored in glioma models harboring IDH1-R132H in the context of ATRX and TP53 loss. Our data demonstrate that co-administering αPD-L1 immune checkpoint blockade with IDH1-R132H inhibition and SOC markedly enhances the overall survival of mIDH1 glioma–bearing mice. Furthermore, this treatment strategy reduces T cell exhaustion and promotes the generation of memory CD8+ T cells, leading to immunological memory. Collectively, our findings demonstrate that upon metabolic reprogramming it is possible to elicit anti–mIDH1 glioma immunity, leading to increased MS and antitumor immunological memory. Our data support the clinical testing of IDH1-R132H inhibitors in combination with SOC and αPD-L1 immune checkpoint blockade to treat glioma patients expressing IDH1-R132H in the context of TP53, ATRX inactivating mutations.

The lecture will be followed by a get together.

With best wishes
Tomasz Wypych