Background As tumor genomes are shaped by their interaction with the immune system, a phenomenon known as immunoediting, it is critical to understand how immunotherapies impact this process. Checkpoint inhibitors directly influence T cells responding to neoantigens, as such, these therapies drastically affect the genomes of surviving tumor clones. Similar to the concept of immune camouflage, observed in infectious diseases, where genomes of pathogens evolve in a way to avoid immune detection, we hypothesized that tumor clones surviving checkpoint inhibition therapy harbor mutations more prone to immune avoidance.
Methods We analyzed a cohort of nivolumab-treated melanoma patients (n=41) for which tumor samples were collected from the same site prior (”Pre” samples) and during (”On” samples) nivolumab therapy.1 The immunogenic and tolerance potential of mutations from the Pre and On samples were evaluated with the Ancer neoantigen screening platform,2 which includes the EpiMatrix algorithm to identify HLA-I and HLA-II neoepitopes and the JanusMatrix algorithm to evaluate neoepitopes homology with self. Prior work with JanusMatrix showed epitopes highly homologous to self can be inhibitory.3 Matching Pre and On therapy samples were compared to identify mutations deleted (unique to the Pre samples), maintained (found in both the Pre and On samples), and induced while on therapy (unique to the On samples).
Results Mutations from the On therapy samples had a lower immunogenic potential than mutations found in the Pre therapy samples (figure 1A, Mann-Whitney test, p=0.0001). After further distinguishing mutations deleted, maintained, and induced while on therapy, we observed that newly induced mutations had a significantly lower immunogenic potential compared to other mutations (Kruskal-Wallis test, p<0.0001). In addition, newly induced mutations were more homologous to self than other mutations (figure 1B, Kruskal-Wallis test, p<0.0001), indicating a greater likelihood for these new mutations to be tolerated by the immune system. In summary, we showed that mutations generated after nivolumab therapy are less immunogenic and more tolerated than mutations found prior to therapy.
Conclusions Our Ancer analysis suggests that nivolumab therapy affects the immunogenicity and tolerance profiles of newly generated mutations in a manner that is consistent with the concepts of immunoediting and immune camouflaging. Mutations induced after therapy appear less immunogenic and more self-like, illustrating a potential mechanism tumors employ to avoid immune surveillance. Furthermore, our approach highlights in silico tools can distinguish effector from tolerance inducing neoepitopes, a critical feature for designing novel neoantigen-based precision immunotherapies.
Riaz N, Havel JJ, Makarov V, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017 November 2;171(4):934–949.
Richard G, De Groot AS, Steinberg GD, et al. Multi-step screening of neoantigens’ HLA- and TCR-interfaces improves prediction of survival. Sci Rep 2021 May 11;11(1):9983.
De Groot AS, Rosenberg AS, Miah SMS, et al. Identification of a potent regulatory T cell epitope in factor V that modulates CD4+ and CD8+ memory T cell responses. Clin Immunol 2021 Mar;224:108661
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