![]() ![]() 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. ![]() 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. Electronic address: & aims:Ĭolorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). Electronic address: 17 Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom. 16 School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.15 Department of Gastrointestinal Oncology, University College London Hospital National Health Service Foundation Trust, London, United Kingdom.14 Department of Histopathology, University College London Cancer Institute, London, United Kingdom.13 School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom Protein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom.12 Drug Development Unit, Sarah Cannon Research Institute UK, London, United Kingdom Department of Oncology, University College Hospital, London, United Kingdom.11 Drug Development Unit, Sarah Cannon Research Institute UK, London, United Kingdom.10 Medical Oncology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom.9 FASTBASE Solutions S.L, Derio, Spain Cell Biophysics Laboratory, Ikerbasque, Basque Foundation for Science, Research Centre for Experimental Marine Biology and Biotechnology & Biophysics Institute, University of the Basque Country, Leioa, Bizkaia, Spain Centre for Therapeutic Innovation, Cell Biophysics Laboratory, Department of Pharmacy and Pharmacology & Department of Physics, University of Bath, Bath, United Kingdom.8 FASTBASE Solutions S.L, Derio, Spain.7 School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.6 Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom.5 Advanced Sequencing Facility, The Francis Crick Institute, London, United Kingdom.4 Experimental Histopathology, The Francis Crick Institute, London, United Kingdom.3 State-Dependent Neural Processing Laboratory, The Francis Crick Institute, London, United Kingdom.Thomas' National Health Service Trust, London, United Kingdom. 2 Biomedical Research Centre, Guy's and St.1 Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom. ![]()
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