A wide number of biomarkers have been associated with immune checkpoint inhibitor (CPI) response to date, however clarity on their reproducibility across larger patient cohorts with defined response criteria is lacking. In addition, systematic pan-tumor analyses may reveal the relative importance of tumour cell intrinsic and microenvironmental features underpinning CPI sensitization.
Here we collated raw whole exome sequencing and transcriptomic data on >1000 patients treated with checkpoint inhibitor (CPI) treatment across eight tumor types (CPI1000+ cohort), utilizing a uniform bioinformatics pipeline. In addition harmonized RECIST response measures were collected from each study to allow standardized clinical outcome analysis. A systematic literature search was conducted to identify previously published biomarkers, which were then tested across the >1000 patient cohort via meta-analysis. Finally, single cell sequencing of tetramer positive T cells from patient tumour tissue was conducted to further validate results.
Clonal-TMB was the strongest predictor of CPI response, followed by TMB and
We find that high clonal mutation burden, apobec/UV/tobacco mutation signatures, together with elevated
The authors.
CRUK, MRC.
K.R. Litchfield: Honoraria (self): Roche. S. Quezada: Full/Part-time employment: Achilles Tx. C. Swanton: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Illumina; Advisory/Consultancy: Genentech; Advisory/Consultancy: Roche-Ventana; Advisory/Consultancy: GRAIL; Advisory/Consultancy: Medicxi; Advisory/Consultancy: Sarah Cannon Research Institute; Shareholder/Stockholder/Stock options: Apogen Biotechnologies; Shareholder/Stockholder/Stock options: Epic Bioscience; Shareholder/Stockholder/Stock options: GRAIL; Leadership role, Shareholder/Stockholder/Stock options: Achilles Therapeutics. All other authors have declared no conflicts of interest.