856 Unlocking the potential of hypoxia reduction in reshaping the glioblastoma tumor microenvironment for enhanced therapeutic synergy

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Background Glioblastoma (GBM) tumors are resistant to most cancer therapies largely due to their highly immunosuppressive tumor microenvironment (TME).1 Hypoxia exacerbates this immunosuppression by upregulating the hypoxia-inducible factor (HIF) pathway in glioma-associated myeloid cells (GAMs) which suppressively polarizes them to maintain this immune ‘cold’ state.2 Tumor hypoxia and hypoxia-driven GAM suppressive programming hinder CD8+ T cell infiltration and effector function by inducing metabolic dysfunction.3 As a result, hypoxia-mediated immunosuppression increases resistance to T cell immune checkpoint blockade (ICB) making hypoxia reduction a viable strategy to overcome drug resistance. Our previous work demonstrated that evofosfamide (TH-302; IMGS-101), a hypoxia-activated prodrug, mitigates tumor progression by reducing immunosuppressive myeloid-derived suppressor cells and alleviating CD8+ T cell suppression in a checkpoint blockade-resistant prostate cancer model.4 Consequently, we aim to elucidate the potential of ablating tumor hypoxia to reshape the immune landscape within GBM tumors by targeting hypoxia-induced immunosuppressive mechanisms. Methods Orthotopic GL261 and CT2A GBM tumors were implanted in mice and the hypoxia-activated prodrug evofosfamide was administered intraperitoneally to diminish tumor hypoxia. We evaluated the efficacy of hypoxia reduction and characterized the spatiotemporal distribution of immune cells through immunofluorescence imaging. Additionally, we conducted survival analysis and performed high-parameter flow cytometry to profile changes in the tumor immune microenvironment post-evofosfamide treatment. Results Evofosfamide administration significantly reduced tumor hypoxia and improved survival in both the GL261 and CT2A GBM models. Treatment with evofosfamide led to increased CD8+ T cell infiltration and cytotoxicity within the tumor, along with a diminished exhaustion phenotype. These CD8+ T cells demonstrated enhanced ex vivo tumor cell killing capability. Furthermore, evofosfamide treatment promoted proliferation and upregulation of pro-inflammatory M1 markers such as CD80 and iNOS. Microglia from evofosfamide-treated tumors also exhibited a decreased capacity to suppress CD8+ T cells ex vivo. Conclusions Our findings demonstrate that GBM tumor hypoxia reduction reshapes the immune microenvironment by enhancing CD8+ T cell infiltration and cytotoxicity and repolarizing microglia towards a less suppressive state. This study is expected to bridge a crucial knowledge gap concerning the effects of tumor hypoxia on the immune system in GBM. It highlights the promising potential of hypoxia reducing agents like evofosfamide to both augment traditional therapies and to sensitize GBM to immunotherapy. Additionally, these studies of hypoxia reduction are elucidating the cellular and molecular mechanisms by which hypoxia reshapes the GBM TME, potentially revealing new targets for future therapeutic interventions. References Incekara F, Smits M, van der Voort SR, et al. The Association between the extent of glioblastoma resection and survival in light of MGMT promoter methylation in 326 patients with newly diagnosed IDH-wildtype glioblastoma. Front Oncol 2020;10:1087. Published 2020 Jul 10. doi:10.3389/fonc.2020.01087. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation [published correction appears in cell. 2003 May 2;113(3):419]. Cell 2003;112(5):645–657. doi:10.1016/s0092-8674(03)00154-5. Scharping NE, Rivadeneira DB, Menk AV, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol 2021;22(2):205–215. doi:10.1038/s41590-020-00834-9. Jayaprakash P, Ai M, Liu A, et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi:10.1172/JCI96268. Ethics Approval The housing of all mice adhered to the standards of the Association for Assessment and Accreditation of Laboratory Animal Care and NIH. Experiments followed approved protocols by the Institutional Animal Care and Use Committee of the University of Texas MD Anderson Cancer Center.

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