Aim1: Somatic mutations and immune escape
Tumor cells contain a number of alterations in their DNA, which are denominated somatic mutations, and provide numerous advantages to the cancer cells, including increased survival/proliferation and resistance to cell death. These changes should be detected by immune surveillance and eliminated before cancer develops. However, the tumor may also get additional mutations evading immune surveillance and allowing the development of an overt disease.
Our first aim is to study somatic mutations in recurrently mutated genes with a special focus in those related to immune escape in FL and DLBCL. Interestingly, there is a connection between specific somatic mutations and a permissive tumor microenvironment. In fact, some of these mutations affect genes involved in the activation of T lymphocytes, which play a major role in the immune response. Accordingly, most FL patients present a mutation in CREBBP gene, which decreases the antigen presentation ability of B cells, a requisite for a successful immune response. Another example is the TNFRSF14 gene, which is inactivated in 18% of patients. This leads to an increase recruitment of T follicular helper cells (TFH) and activation of FL cell proliferation.
Using a lymphoid next generation sequencing (NGS) custom panel designed at Hospital Clínic, we will be able to better characterize how FL tumors avoid immune response, an important aspect to establish new immunotherapeutic approaches.