Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors

Luis Zapata, Giulio Caravagna, Marc J. Williams, Eszter Lakatos, Khalid AbdulJabbar, Benjamin Werner, Diego Chowell, Chela James, Lucie Gourmet, Salvatore Milite, Ahmet Acar, Nadeem Riaz, Timothy A. Chan, Trevor A. Graham, Andrea Sottoriva

Research output: Contribution to journalArticlepeer-review


In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.

Original languageEnglish
Pages (from-to)451-460
Number of pages10
JournalNature Genetics
Issue number3
StatePublished - Mar 2023


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