Characterization of immune escape mechanisms associated with tumor progression and resistance to chemotherapy – TERMM

Cancer is one of the most prominent public health challenges, and colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. Although recent developments in cancer therapy have a significant clinical impact, only a subset of patients exhibit long-term clinical responses and the rationale selection of treatment for CRC patients should be improved. Therefore, a better understanding of the molecular and cellular immune escape mechanisms leading to tumor progression and resistance to therapy is necessary. It is known that the tumor microenvironment (TME), and in particular the Immunoscore, has a profound impact on tumor development and on response to chemotherapy. Host-derived factors can also mediate immune escape mechanisms. Indeed, there exists increasing evidence that tumor-intrinsic signaling and immune modulatory molecules play a key role in regulating the immune suppressive TME and immune escape. We here propose to perform an in-depth analysis of the CRC landscape to (1) decipher the immune mechanisms associated with response to chemotherapy in CRC patients and (2) unravel the mechanisms underlying the immune control of cancer progression, spanning from stage II to the metastatic stage IV. We will study the immune landscape of the TME as well as genomics, immunomics and miRNA alterations in tumor cells by exploiting access to large collections of human samples using state-of-the-art technologies. The role of immune modu-latory molecules, e.g. HLA class I APM components, HLA-G and PD-L1, will also be explored. On one hand, by comparing CRC patients treated or not with chemotherapy, we expect to reveal intrinsic and/or extrinsic escape mechanisms in non-responding patients. On the other hand, by assessing the tumor immune landscape in CRC patients from stage II to IV, we expect to identify mechanisms of cancer progression and recurrence, especially at the metastatic stage. The data obtained will then be correlated with the Immunoscore classification of CRC patients in order to understand the mechanisms associated with high and low Immunoscore at all stages of this disease as well as factor(s) associated with response to chemotherapy. This analysis should allow to identify prognostic and predictive biomarkers, which not only will have an impact on the understanding of immune escape mechanisms, but also on cancer classification, and on the development of therapies for better patient clinical management.