The rise and fall of metastatic clones under immune attack

ended

Colorectal cancer is the second most common cancer in Europe, and although screening has drastically increased survival, a fraction of patients still develops metastatic disease. These patients have a 5-year survival rate of 14% compared to 70% for those non-metastatic (SEER 18). For the majority of cases, the primary tumour is successfully resected, but disease relapse arises due to undetectable metastases. How metastatic clones arise within the primary tumor and adapt to their microenvironment acquiring the capacity of colonize new niches remain unknown. In this project, we aim to use evolutionary analysis combined with state of the art high-throughput technologies to analyse the relationship between the immune system and the progression to metastatic disease. Recently, Zapata and colleagues analysed the relationship between natural selection and the immune system using more than 20 publicly available cancer datasets. The results demonstrated that the presence of neoantigens in the course of tumour development is constrained by the strength of immune activity (immunoediting). In metastasis, malignant clones must escape immune surveillance to colonise new environments. Therefore, we hypothesize that the presence of neoantigens under negative selection in primary tumours will inform us of the cancer cells' ability to disseminate, and ultimately, settle in distant niches. To test our hypothesis, we will develop a patient- specific method to quantify immunoediting across three different cohorts of primary-metastasis matched samples. Ultimately, the extent of immunoediting can be used to explain the underlying causes of metastatic progression allowing, in the future, the development of better treatment strategies.