Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but underlying mechanisms and instigators that initiate tumor hypoxia remain unclear. We tracked tumor hypoxia in GBM in mice using a sensitive fluorescent reporter. We revealed that tumor hypoxia functions as a critical link between immune cells and tumor cells that drives malignant potency and immunosuppression in GBM. Single-cell RNA sequencing analysis revealed that hypoxic GBM cells are quiescent, display a mesenchymal transition, are more represented in recurrent GBM and predict worse patient outcome. Interestingly, the in vivo GBM hypoxia gene signatures surprisingly showed an enrichment for immune pathways. We unveiled two potential mechanisms of hypoxia-induced immunosuppression: by sequestrating activated immune cells in hypoxia zones, thus limiting inflammatory spread and cutting off immune cell communication, and by reprograming entrapped immune cells towards an immunotolerant state. Reciprocally, entrapped TAMs release CCL8 and IL1β as hypoxic niche factors that not only reinforce immune cell retainment in hypoxic cores, but also shape the transcriptional response of hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Altogether, our study revealed a reciprocal influence of anticancer immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM.

Citation Format: Anirudh Sattiraju, Valerie Marallano, Zhihong Chen, Sangjo Kang, Concetta Brusco, Aarthi Ramakrishnan, Li Shen, Dolores Hambardzumyan, Roland H. Friedel, Hongyan Zou. Reciprocal influence of immune response and tumor hypoxia during glioblastoma progression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P022.