Cancer immunotherapies, notably those based on immune checkpoint blockade, have shown unprecedented rates of clinical responses. However,these successes have been seriously challenged by clinical observations showing that the majority of patients reap a short-term benefit or no benefit at all. The failure in achieving a sustained and durable clinical response likely depends on the establishment of an immunosuppressive microenvironment, which limits the infiltration of cytotoxic immune cells. It is well defined that hypoxia plays a major role in the establishment of such immunosuppressive tumor microenvironment. Therefore, finding best strategies to target intratumoral hypoxia constitutes a key issue to achieve a successful anti tumor immune response. This project aims to address three major issues: i) Temporal monitoring of the establishment of intratumoral hypoxia in well characterized preclinical mouse models (melanoma and mammary carcinoma) and evaluation of the impact of hypoxic stress on the immune landscape of tumors; ii) Evaluation of the relative contribution of hypoxia inducible factors (HIF)-1 and/or -2 on the establishment of the intratumoral hypoxia; iii) Finding of the best strategies to target or alleviate the intratumoral hypoxia and evaluation of its therapeutic benefits for the use of immune checkpoint blockade based on anti-PD-1/PD-L1. The ultimate goal of this study is to provide innovative and cutting-edge approaches to improve and formulate more effective PD-1/PD-L1 based anticancer immunotherapies and provide the proof of concept to set up further clinical trials based on the combination of hypoxia modulators and immune checkpoint blockade.
|Effective start/end date||1/10/17 → 30/09/20|
- FNRS - Fonds National de la Recherche Scientifique: €178,451.00
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