Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

Scott D. Brown; Rene L. Warren; Ewan A. Gibb; Spencer D. Martin; John J. Spinelli; Brad H. Nelson; Robert A. Holt

doi:10.1101/gr.165985.113

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

¹Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
²Genome Science and Technology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
³Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
⁴Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia V8R 6V5, Canada;
⁵Cancer Control Research Program, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada;
⁶School of Population and Public Health, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
⁷Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada;
⁸Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada

Abstract

Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient’s autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies.

Footnotes

↵9 Corresponding author

E-mail rholt{at}bcgsc.ca
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.165985.113.

Freely available online through the Genome Research Open Access option.

Received August 30, 2013.
Accepted February 21, 2014.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.