Landscape ANalyses of immune CEll signatures associated with early Liver metastatic cOlorecTal cancer (LANCELOT)

More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CRLM) that are characterized by poor prognosis and lack of reliable prognostic markers. CRLM occurrences involve multiple aspects of host immunity including innate and adaptive immune cells. Indeed, the Immunoscore system was recently proposed as an indicator of CRC patient prognosis and metastases formation, thus indicating this system as a potential candidate for screening immunotherapy. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration T cells, while information concerning other immune cell types is still absent. Indeed, other cell-types such as B cells, unconventional T cells (MAIT, NKT, gamma delta T cells) and innate cell types including dendritic cells and macrophages can still influence CRLM progression. Therefore, in comparison with the Immunoscore system, comprehensive immune landscape profiling appears to be more promising, mainly due to the high variability of local, primary and metastatic tumors, immune infiltrates. In addition, targeting both adaptive and innate immune cells offer an alternative immunotherapeutic option. However, there is no comparison of specific adaptive and innate features of the matched gut and liver tumors in CRLM disease in the context of clinical translation. On these bases, we propose a project of translational medicine investigating the immune-profiles of gut and liver tumor micro-environments in an autologous setting from patients undergoing to the simultaneous surgical removals of primary and metastatic tumours. Our working hypothesis is that the local interactions between immune and malignant cells in early stage of CRLM defines and predicts tumor-escape, thus implying different efficacies of novel immunotherapies such as the administration of immune checkpoint inhibitors. The strength of our proposal relies on the multidisciplinary approaches merging clinical and immunological expertise through the use of new powerful technologies adopting an unprecedented degree of single cell resolution analysis. In particular, we rely on: a) a unique expertise in the field of clinical, immunological and oncologic features of CRC and CRLM; b) the possibility of simultaneously collect gut and liver specimens from CRLM patients undergoing surgical procedures; c) perform computational analysis by using single cell RNA-sequencing and single cell T cell receptor (TCR)-sequencing data. This experimental strategy will allows to dissect the immune mechanisms of CRC progression to CRLM with the aim to find more effective and targeted immuno-therapies.