To model how immune-proficient and immune-deficient tumors evolved, Łuksza, Sethna, and Rojas et al. compared primary and recurrent tumors from long-term survivors (LTSs) and short-term survivors (STSs) of human pancreatic cancers and found that LTSs have fewer and more homogeneous recurrent tumors. LTS tumors contained both fewer new neoantigens and new clones, with markedly lower immune fitness cost compared with recurrent STS tumors. Mutations with a greater antigenic distance from self were more significantly depleted in LTS PDAC, suggesting that immune selection in LTS tumors edited clones with high-quality neoantigens.
Contributed by Shishir Pant
ABSTRACT: Cancer immunoediting(1) is a hallmark of cancer(2) that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice(1,3), whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness' based on neoantigen similarity to known antigens(4,5), and 'selfness' based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.