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

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Presentation transcript:

Fig. 1. Genomic landscape of serial tumor biopsies and genomic and immune correlates of treatment response. Genomic landscape of serial tumor biopsies and genomic and immune correlates of treatment response. (A) Patients with metastatic melanoma were initially treated with CTLA-4 blockade (n = 56; asterisk indicates that 2 of the 56 patients were CTLA-4 blockade–naïve). Both responded to PD-1 blockade, and only pretreatment samples were available for WES and TCR-seq. Nonresponders (NRs) to CTLA-4 blockade (n = 47) were then treated with PD-1 blockade. Double nonresponders (DNRs) progressed on CTLA-4 blockade first and then progressed on PD-1 blockade. Serial tumor biopsies were collected at multiple time points (pretreatment, early on-treatment, and progression on CTLA-4 blockade and PD-1 blockade) when feasible. WES and TCR-seq were performed on these serial tumor biopsies. The numbers in parentheses indicate the number of samples available for responders (Rs) and nonresponders after quality control of WES and TCR-seq data. (B) For each sample (columns), genomic profiles (rows) were characterized. Column annotations represent biopsy time (pre–αCTLA-4, pre–CTLA-4 blockade samples; pre–αPD-1, pre–PD-1 blockade samples; post–αPD-1, post–PD-1 blockade samples) and response status (red, responders; blue, nonresponders; asterisk indicates 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; E, post–PD-1). Mutational burden and neoantigen burden for each sample are shown at the top of the panel. Neoantigens were defined as having a median inhibitory concentration (IC50) <500 nM. Color scale shows the range of IC50 from 500 to 50 nM. Synonymous (light) and nonsynonymous (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 > frameshift indel > splice site mutation > missense mutation > in-frame indel. (C) Boxplots summarize TCR clonality by response status (blue, nonresponders; red, responders) in pre–CTLA-4 blockade samples, pre–PD-1 blockade samples, on–CTLA-4 blockade samples, and on–PD-1 blockade samples; median values (lines) and interquartile range (whiskers) are indicated. P values were calculated using 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). Whijae Roh et al., Sci Transl Med 2017;9:eaah3560 Published by AAAS