In a joint effort between the Centre for Evolution and Cancer at The Institute of Cancer Research in London and the Computational Biology Research Centre at Human Technopole in Milan, researchers delved into the intricate relationship between immune selection, tumour development, and the effectiveness of checkpoint inhibitor therapies. This interdisciplinary study sheds light on important factors that can impact cancer treatment strategies. The focus of this study lies in the ongoing battle within the human body, where cancer cells strive to evade the immune system's watchful gaze and establish themselves. With an extensive dataset encompassing over 10,000 primary tumours and 356 immune-checkpoint-treated metastases, researchers employed a metric known as immune dN/dS. This metric quantifies the ratio of mutations that lead to changes in amino acid sequences (nonsynonymous mutations) to those that do not (synonymous mutations) within the immunopeptidome. This term refers to the genomic regions responsible for generating peptides that the immune system can recognise – a pivotal factor in assessing the level of immune selection at both individual and group levels.

Through this comprehensive analysis, the study uncovers two primary categories of tumours: immune-edited and immune-escaped. Immune-edited tumours engage in a strategic process of shedding antigenic mutations through negative selection, providing a level of protection against immune attacks. On the other hand, immune-escaped tumours adopt an alternative approach by masking their antigenic features through abnormal immune modulation. A significant observation emerges: only immune-edited tumours demonstrate a clear correlation between immune predation and the infiltration of CD8 T cells – essential components of the immune response against cancer. In immunotherapy-treated tumours, it becomes evident that immune-escaped metastases exhibit the most promising response to immunotherapy interventions. Conversely, patients with immune-edited tumours do not experience the same positive outcomes, suggesting the presence of inherent resistance mechanisms. This observation is further reinforced by an analysis of patients undergoing nivolumab treatment, where the therapy exclusively targets and eliminates neoantigens from the immunopeptidome of nonimmune-edited patients – those displaying the most favourable overall survival response. This study underscores the urgent need to comprehend tumour evolutionary dynamics for the purpose of developing precise and effective personalised medicine strategies. While traditional predictive biomarkers like tumour mutation burden (TMB), microsatellite instability (MSI), and PDL1 expression remain invaluable, they lack the complexity needed to capture the intricate interactions between tumours and the immune system. This study emphasises the importance of refining our analytical metrics to account for the intricate interplay between these factors.

The nonsynonymous to synonymous mutations ratio, or dN/dS – a metric often used to decode selection processes in cancer. However, this study takes a novel approach, utilising dN/dS within the framework of the self-immunopeptidome. This strategic manoeuvre allows for a deeper understanding of immune selection and its impact on T cell infiltration in primary immune-edited tumours. The self-immunopeptidome – encompassing genomic regions responsible for generating immune-interacting peptides – emerges as a pivotal focal point for unravelling the complexities of immune selection. However, the intricate interplay between immune selection and negative selection in cancer sparks robust discussions. While some studies advocate for a clear link between immune activity and selective pressures, differing viewpoints question the validity of such claims. In response, this study promotes a nuanced understanding, highlighting the potential loss of vital immune selection signals when tumours are not classified into immune-edited and immune-escaped categories.

In essence, this study unravels the intricate web of interactions that define cancer's progression. Through the lens of interdisciplinary collaboration, this research lays the groundwork for a future where personalised medicine is driven by a deep understanding of the dynamic interplay between tumour evolution and the body's immune defences.