Abstract
Recurrent tumors in long-term survivors of pancreatic cancer have less high-quality neoantigens.
Major Finding: Recurrent tumors in long-term survivors of pancreatic cancer have less high-quality neoantigens.
Concept: A fundamental role of the human immune system involves surveillance of genetic change to suppress cancer.
Impact: These results support prediction of how cancers evolve and the immune system's role in this process.
Through the process of cancer immunoediting, tumor cell clones that express less immunogenic neoantigens are selected for and contribute to cancer outgrowth; however, definitive evidence for this process in the evolution of human cancers has yet to be confirmed. Łuksza, Sethna, Rojas, and colleagues sought to address this through examination of the 10-year evolution of 70 pancreatic ductal adenocarcinomas (PDAC) from 15 patients, which showed long-term survivors (LTS) had more homogeneous recurrent tumors than short-term survivors (STS). Examination into the role neoantigen selection pressure plays in this process revealed a similar tumor mutational burden (TMB) between primary LTS and STS tumors, but a much lower TMB in recurrent LTS tumors as well as a lower number of neoantigens. Moreover, expanding upon the previously developed neoantigen quality model, cross-reactivity of a human leukocyte antigen class I epitope was found to be dependent on particular positions and residues within the peptide, specifically cross-reactivity was promoted when mutations occurred at peptide termini or within amino acid biochemical families. Furthermore, peptides with mutations leading to a greater antigenic distance from self were most depleted in LTS tumors, suggesting the selectivity of high-quality neoantigen loss in this tumor subset. To predict these immunoedited tumor cell clones, neoantigen quality was used to quantify the negative selection of neoantigen immune recognition and was incorporated into a fitness model, which also accounted for the positive selection of oncogenic driver mutations. Findings using this model showed a reduction in new neoantigens and immune fitness cost in recurrent LTS tumors as compared to recurrent STS tumors. In summary, this study shows that tumors that evolve under stronger immune pressure lose more immunogenic neoantigens and supports the function of the human immune system naturally editing neoantigens in cancer. Additionally, in contrast to conventional wisdom, mutation-derived neoantigens were shown to be targets of the immune system even in low-mutated cancers like PDAC, providing rationale for use of neoantigen-based therapies to activate immunity in low-mutated cancers.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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