Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Proffered Paper - Translational research

1928O - Meta-analysis of tumour and T cell intrinsic mechanisms of sensitization to checkpoint inhibition


19 Sep 2020


Proffered Paper - Translational research


Tumour Immunology;  Translational Research

Tumour Site


Kevin Litchfield


Annals of Oncology (2020) 31 (suppl_4): S1034-S1051. 10.1016/annonc/annonc294


K.R. Litchfield1, J. Reading2, N. McGranahan3, S. Quezada4, C. Swanton5

Author affiliations

  • 1 Swanton Lab, Francis Crick Institute, NW1 1AT - London/GB
  • 2 Cancer Institute, University College London, WC1E 6DD - London/GB
  • 3 Cancer Institute, UCL Cancer Institute/Paul O'Gorman Building, WC1E 6JD - London/GB
  • 4 Cancer Institute, University College London, WC1E 6JD - London/GB
  • 5 Translational Cancer Therapeutics Department, The Francis Crick Institute, NW1 1AT - London/GB


Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 1928O


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 CXCL9 expression. Subclonal-TMB, somatic copy alteration burden and HLA-evolutionary divergence failed to attain significance. Mutation signature analysis revealed apobec, UV and tobacco associated mutations predictive of CPI response even after correction for TMB. scRNA sequencing of clonal neoantigen-reactive CD8-TILs, combined with bulk RNAseq analysis of CPI responding tumors, identified CCR5 and CXCL13 as T cell-intrinsic mediators of CPI-sensitisation. Finally, combination of biomarkers together into a multi-variate predictive algorithm was shown to attain siginificantly higher AUC scores than TMB alone, in both validation (n=406) and independent test set (n=383).


We find that high clonal mutation burden, apobec/UV/tobacco mutation signatures, together with elevated CXCL9 and CXCL13 expression, as core features marking a tumor as likely to respond to CPI therapy. As biomarker datasets continue to grow in size there is tangible opportunity to build a more complete understanding of CPI response, and identify molecularly defined patient cohorts with high chance of response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.




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.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.