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. Author manuscript; available in PMC: 2018 Feb 20.
Published in final edited form as: Sci Transl Med. 2017 Mar 1;9(379):eaah3560. doi: 10.1126/scitranslmed.aah3560

Fig. 1. Genomic landscape of serial tumor biopsies and genomic and immune correlates of treatment response.

Fig. 1

(A) Patients with metastatic melanoma were initially treated with CTLA-4 blockade (n=56*: * indicates that two of the 56 patients were CTLA-4 blockade naïve. Both responded to PD-1 blockade, and only pre-treatment samples were available for WES and TCR-seq). Non-responders to CTLA-4 blockade (n=47) were then treated with PD-1 blockade. Double non-responders progressed on CTLA-4 blockade first and then progressed on PD-1 blockade. Serial tumor biopsies were collected at multiple time points (pre-treatment, early on-treatment, and progression on CTLA-4 blockade and PD-1 blockade, respectively) when feasible. Whole exome sequencing and TCR sequencing were performed on these serial tumor biopsies. The numbers in parentheses indicate the number of samples available for responders and non-responders after quality control of WES and TCR-seq data. R: responders, NR: non-responders, DNR: double non-responders. (B) For each sample (columns), genomic profiles (rows) were characterized. Column annotations represent biopsy time (Pre-αCTLA4: pre-CTLA-4 blockade samples, Pre-αPD1: pre-PD-1 blockade samples, Post-αPD1: post-PD-1 blockade samples) and response status (red: responders indicated as R, blue: non-responders indicated as NR, *: failed CTLA-4 blockade but responded to PD-1 blockade) for each sample (Sample ID denotes patient ID followed by biopsy time: A=pre-αCTLA-4, C=post-CTLA-4/pre-PD-1, and E=post-PD-1). Shown at the top of the panel is mutational burden and neoantigen burden for each sample. Neoantigens were defined as having an IC50<500nM. Color scale shows the range of IC50 from 500nM to 50nM. Synonymous (light) and non-synonymous (dark) mutations are shown in different shades of blue. Additional genomic profiles included selected somatic point mutations, and indels. No indels were found among melanoma driver genes. When multiple mutations were found in one gene, the following precedence rule was applied: Nonsense mutation > Frame-shift indel > Splice site mutation > Missense mutation > In-frame indel. (C) Boxplots summarize TCR clonality by response status (blue: non-responders, red: responders) in pre-CTLA-4 blockade samples, pre-PD-1 blockade samples, on-CTLA-4 blockade samples, and on-PD-1 blockade samples, respectively; median values (lines) and interquartile range (whiskers) are indicated. P values were calculated using a two-sided Mann-Whitney U test (P > 0.05 for TCR clonality in pre-CTLA-4 blockade and on-CTLA-4 blockade samples, P = 0.041 for TCR clonality in pre-PD-1 blockade samples and P = 0.032 for TCR clonality in on-PD-1 blockade samples.).