Reprogramming the fibroblast-neutrophil axis in colorectal cancer (360G-Wellcome-313599_Z_24_Z)

Colorectal cancer (CRC) is the second most common form of cancer and second leading cause of cancer-related death in Europe. Despite promising advances in immune checkpoint inhibitors, the majority of CRC patients show resistance to immunotherapies due to the suppressive microenvironment generated by immune cells, cancer associated fibroblasts (CAFs) and the tumour extracellular matrix (ECM). Among the immune landscape of CRC, tumour associated neutrophils (TANs) are particularly interesting as therapeutic targets for their phenotypic plasticity, presenting both anti-tumoural and immunosuppressive functions. Reprogramming TANs in CRC could therefore constitute an effective strategy to sensitise the tumour to immunotherapies, however, we must first understand how the crosstalk between TANs and the tumour microenvironment drives their immunosuppressive polarisation. In this project, I propose to address this critical healthcare challenge using a multidisciplinary approach to investigate how targeting the crosstalk between CAFs, TANs and the ECM can reprogram their interaction towards an immunotherapeutic function. To this end, I will: 1) characterise the mechanisms of CAF and TAN plasticity and interaction, 2) investigate the role of ECM remodelling and mechanosignalling on TAN polarisation, and 3) assess the therapeutic potential of reprogramming the CAF-ECM-TAN axis in a CRC-on-a-chip microfluidic platform.