Understanding tumour-immune interactions and cancer immunotherapy responses from differential immune selection pressures in the cancer genome

The human immune system has a key role in preventing tumour formation. This long-standing immunosurveillance theory has been reinforced in recent years due to the success of cancer therapies that modulate the immune system (immunotherapy). Cancer cell immune recognition is mainly mediated by neoantigens, small mutated peptides that are presented to immune cells at the cancer cell membrane via the Major Histocompatibility Complex type I (MHC-I). While immune-mediated cancer cell elimination is expected to impose a strong immune selective pressure on the underlying mutations, resulting in the depletion of neoantigens in primary tumours, we demonstrated a surprising lack of such neoantigen depletion signals in cancer genome sequencing data. During the first phase of  my PhD, I identified a selection-independent intrinsic association between oncogenicity and immunogenicity of a set of common cancer hot spot mutations such as BRAF V600E. Because emerging evidence suggests an important role for noncanonical, MHC-II (presentable) neoantigens in human carcinogenesis, the underlying somatic mutations could be important modulators of tumour-immune interactions and immunotherapy. During the last phase of my PhD and in the proposed project I intend to perform a systematic analysis on selection signals in MHC-II neoantigen forming mutations and determine their value as a biomarker for immunotherapy responses. Besides the acquired fundamental insights in tumour-immune interactions, results from the PhD project will be valuable for future immunotherapy response predictions and rational (combinatorial) anti-cancer treatment selection.