Triple

-negative breast cancer (TNBC) represents 15–20% of all breast cancers (BC) and has the worst outcome of all BC subtypes. Although anti-PD-L1 immune checkpoint blockade (ICB) combined with chemotherapy can improve the outcome only for some patients, clinical benefits remain modest and restricted to a subset of patients. Consequently, there is an important need to define biomarkers that more effectively identify patients who will benefit from ICB and to improve treatment strategies for those with no benefit.

To address these challenges, we will characterize the tumor microenvironment (TME) of human TNBC samples before and after immunotherapy using multi-omics analysis of primary and metastatic lesions from 2 randomized phase II clinical trials led by our consortium: the GeparNuevo trial investigating the addition of anti-PD-L1 (durvalumab) to standard neoadjuvant chemotherapy in patients with early TNBC, and the SYNERGY trial evaluating the combination of chemotherapy (paclitaxel-carboplatin) with anti-PD-L1 (durvalumab) with or without an anti-CD73 therapy (oleclumab) in patients with advanced TNBC.

Access to paired pre-treatment and on-treatment samples will further provide a unique opportunity to evaluate adaptation of TNBC to immunotherapy and identify novel approaches. Hence, in addition to identifying 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.