TY - JOUR
T1 - Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade
T2 - Analysis of the KEYNOTE 177 Trial and Validation Cohorts
AU - Bortolomeazzi, Michele
AU - Keddar, Mohamed Reda
AU - Montorsi, Lucia
AU - Acha-Sagredo, Amelia
AU - Benedetti, Lorena
AU - Temelkovski, Damjan
AU - Choi, Subin
AU - Petrov, Nedyalko
AU - Todd, Katrina
AU - Wai, Patty
AU - Kohl, Johannes
AU - Denner, Tamara
AU - Nye, Emma
AU - Goldstone, Robert
AU - Ward, Sophia
AU - Wilson, Gareth A.
AU - Al Bakir, Maise
AU - Swanton, Charles
AU - John, Susan
AU - Miles, James
AU - Larijani, Banafshe
AU - Kunene, Victoria
AU - Fontana, Elisa
AU - Arkenau, Hendrik Tobias
AU - Parker, Peter J.
AU - Rodriguez-Justo, Manuel
AU - Shiu, Kai Keen
AU - Spencer, Jo
AU - Ciccarelli, Francesca D.
N1 - Funding Information:
Funding This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001002, FC001169, FC001745, FC001130), the UK Medical Research Council (FC001002, FC001169, FC001745, FC001130), and the Wellcome Trust (FC001002, FC001169, FC001745, FC001130). Francesca D. Ciccarelli is supported by Cancer Research UK (C43634/A25487), Guys and St Thomas Charity (R170504), the European Union’s Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie grant agreement No. CONTRA-766030, the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135), and the Cancer Research UK City of London Centre (C7893/A26233).
Funding Information:
The authors thank Professor Rebecca Fitzgerald (University of Cambridge) and Professor Toby Lawrence (King’s College London) for critical comments to the manuscript. The authors acknowledge technical support from the Advanced Sequencing, the Flow Cytometry and the Experimental Histopathology Platforms of The Francis Crick Institute, the National Institute for Health Research Biomedical Research Centre Immune Monitoring Core Facility Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London, Christopher Applebee and Sánchez-Magraner for the FRET analysis, and Joe Brock for graphical illustrations. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research or the United Kingdom Department of Health. The results published here are in part based upon data generated by The Cancer Genome Atlas managed by the National Cancer Institute and National Human Genome Research Institute. WES (EGAD00001006165) and RNA sequencing (EGAD00001006164) data have been deposited in the European Genome-phenome Archive. TCR-seq ( https://doi.org/10.5281/zenodo.3744371 ) and IMC ( https://doi.org/10.5281/zenodo.3743253 ) data have been deposited in Zenodo. The code used in this study and all supporting data are available upon request.
PY - 2021/10/31
Y1 - 2021/10/31
N2 - Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy. Methods: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME. Results: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages. Conclusions: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.
AB - Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy. Methods: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME. Results: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages. Conclusions: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.
KW - Anti-PD1 Immunotherapy
KW - CD8 T cells
KW - Interferon Gamma
KW - Tumor Mutational Burden
KW - Wnt Signaling
UR - http://www.scopus.com/inward/record.url?scp=85111546429&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.06.064
DO - 10.1053/j.gastro.2021.06.064
M3 - Article
C2 - 34197832
AN - SCOPUS:85111546429
SN - 0016-5085
VL - 161
SP - 1179
EP - 1193
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -