3/18/2023 0 Comments Keynote 177![]() ![]() The code used in this study and all supporting data are available upon request. TCR-seq ( ) and IMC ( ) data have been deposited in Zenodo. WES (EGAD00001006165) and RNA sequencing (EGAD00001006164) data have been deposited in the European Genome-phenome Archive. 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. 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. Ciccarelli is supported by Cancer Research UK (C43634/A25487), Guys and St Thomas Charity (R170504), the European Unionnchez-Magraner for the FRET analysis, and Joe Brock for graphical illustrations. Note = "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). We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.", It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. Conclusions: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages. ![]() ![]() 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. 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. 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 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. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.Ībstract = "Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1 +CD8 T cells interacting with PDL1 + antigen-presenting macrophages. Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |