MAppinG adaptatioN Of tripLe negative breast cancer microenvironments to ImmunotherApy
Triple-negative breast cancer (TNBC) represents 15–20% of all breast cancers (BC), currently lacks precision therapies and has the worst outcome of all BC subtypes. Although PD-L1 is highly expressed in TNBC and anti-PD-L1 immune checkpoint blockade (ICB) combined with chemotherapy can improve outcome, clinical benefits still remain modest and are restricted to a subset of TNBC patients. PD-L1 expression can be both in tumor cells and/or immune cells as well as localised to tumor subdomains. PD-L1 heterogeneity associates with differential response to ICB, Consequently, there is an important need to provide in depth understanding of the PD-L1 landscape and response to ICB to define biomarkers that more effectively identify patients who will benefit from ICB and improve treatment strategies for those with no benefit. To address these challenges, we propose to define the tumor microenvironment of human TNBC samples before and after ICB using multi-omics analysis of primary and metastatic lesions from 2 randomized phase II clinical trials led by our consortium: the GeparNuevo trial investigating addition of anti-PD-L1 (durvalumab) to standard neoadjuvant chemotherapy in patients with early TNBC, and SYNERGY trial evaluating the combination of chemotherapy (paclitaxel-carboplatin) with anti-PD-L1 (durvalumab) with or without an anti-CD73 therapy (oleclumab to block CD73 immunosuppressive activity) in patients with advanced TNBC. Access to paired pre- and on-treatment samples will provide a unique opportunity to provide in depth understanding of adaptation of TNBC to ICB. In addition to identifying new predictive biomarkers, we will identify and validate new therapeutic targets by employing both a hypothesis-driven and an agnostic approach from our multi-omics analysis. This project will deliver unprecedented detail of the spatial architecture of TNBC that will elucidate pivotal cell interactions driving TNBC behaviour and resistance to immunotherapy
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.