Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors

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2023-03-01

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

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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.

URI

https://hdl.handle.net/11511/102756

Journal

Nature Genetics

DOI

https://doi.org/10.1038/s41588-023-01313-1

Collections

Department of Biology, Article

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Citation Formats

L. Zapata et al., “Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors,” Nature Genetics, vol. 55, no. 3, pp. 451–460, 2023, Accessed: 00, 2023. [Online]. Available: https://hdl.handle.net/11511/102756.