Everybody remembers their first

My first paper! And first author too!

I joined this project started by Rene Warren and Rob Holt in the summer of 2013. Rene had built a lovely pipeline to process TCGA data, and I came on between my undergrad and grad degrees as a summer student to play with and analyze the resulting data. After filtering the processed data to maximize the chance of predicting truly immunogenic mutations (high expression of presenting HLA, high expression of mutated gene, strong binding of mutated peptide to MHC), we found a striking association between the number of predicted immunogenic mutations in a tumour, and the level of T cell infiltrate in a tumour. It was already known that patients with tumours having higher levels of T cell infiltrate had better overall survival, so this result supported the idea that these infiltrating T cells were recognizing tumour neoantigens. Despite these tumours having high numbers of immunogenic mutations, and high numbers of T cells, we also showed that they had high expression of PDCD1 and CTLA-4, which suggest that these T cells may be inhibited. This would explain why these patients, despite having good infiltrate and T cell targets, still had cancer.

Link: http://genome.cshlp.org/content/24/5/743.short

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.