Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors
Journal article, 2023
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.
Author
Luis Zapata
Institute of Cancer Research
Giulio Caravagna
University of Trieste
Institute of Cancer Research
Marc J. Williams
Memorial Sloan-Kettering Cancer Center
Eszter Lakatos
Queen Mary University of London
Khalid AbdulJabbar
Institute of Cancer Research
Benjamin Werner
Barts Cancer Institute
Queen Mary University of London
Diego Chowell
Icahn School of Medicine at Mount Sinai
Chela James
Fondazione Human Technopole
Institute of Cancer Research
Lucie Gourmet
University College London (UCL)
Institute of Cancer Research
Salvatore Milite
University of Trieste
Fondazione Human Technopole
Ahmet Acar
Middle East Technical University (METU)
Nadeem Riaz
Memorial Sloan-Kettering Cancer Center
Timothy A Chan
Cleveland Clinic Foundation
Trevor A. Graham
Institute of Cancer Research
Queen Mary University of London
Andrea Sottoriva
Fondazione Human Technopole
Institute of Cancer Research
Nature Genetics
1061-4036 (ISSN) 15461718 (eISSN)
Vol. 55 451-460Gender Initiative for Excellence (Genie)
The Chalmers University Foundation, 2019-01-01 -- 2028-12-31.
Subject Categories (SSIF 2025)
Bioinformatics and Computational Biology
Cancer and Oncology
Areas of Advance
Health Engineering
DOI
10.1038/s41588-023-01313-1