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Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts.
Bortolomeazzi, Michele; Keddar, Mohamed Reda; Montorsi, Lucia; Acha-Sagredo, Amelia; Benedetti, Lorena; Temelkovski, Damjan; Choi, Subin; Petrov, Nedyalko; Todd, Katrina; Wai, Patty; Kohl, Johannes; Denner, Tamara; Nye, Emma; Goldstone, Robert; Ward, Sophia; Wilson, Gareth A; Al Bakir, Maise; Swanton, Charles; John, Susan; Miles, James; Larijani, Banafshe; Kunene, Victoria; Fontana, Elisa; Arkenau, Hendrik-Tobias; Parker, Peter J; Rodriguez-Justo, Manuel; Shiu, Kai-Keen; Spencer, Jo; Ciccarelli, Francesca D.
Afiliação
  • Bortolomeazzi M; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Keddar MR; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Montorsi L; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Acha-Sagredo A; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Benedetti L; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Temelkovski D; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Choi S; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
  • Petrov N; Biomedical Research Centre, Guy's and St. Thomas' National Health Service Trust, London, United Kingdom.
  • Todd K; Biomedical Research Centre, Guy's and St. Thomas' National Health Service Trust, London, United Kingdom.
  • Wai P; State-Dependent Neural Processing Laboratory, The Francis Crick Institute, London, United Kingdom.
  • Kohl J; State-Dependent Neural Processing Laboratory, The Francis Crick Institute, London, United Kingdom.
  • Denner T; Experimental Histopathology, The Francis Crick Institute, London, United Kingdom.
  • Nye E; Experimental Histopathology, The Francis Crick Institute, London, United Kingdom.
  • Goldstone R; Advanced Sequencing Facility, The Francis Crick Institute, London, United Kingdom.
  • Ward S; Advanced Sequencing Facility, The Francis Crick Institute, London, United Kingdom.
  • Wilson GA; 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.
  • Al Bakir M; 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.
  • Swanton C; 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.
  • John S; School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.
  • Miles J; FASTBASE Solutions S.L, Derio, Spain.
  • Larijani B; 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
  • Kunene V; Medical Oncology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom.
  • Fontana E; Drug Development Unit, Sarah Cannon Research Institute UK, London, United Kingdom.
  • Arkenau HT; Drug Development Unit, Sarah Cannon Research Institute UK, London, United Kingdom; Department of Oncology, University College Hospital, London, United Kingdom.
  • Parker PJ; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom; Protein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom.
  • Rodriguez-Justo M; Department of Histopathology, University College London Cancer Institute, London, United Kingdom.
  • Shiu KK; Department of Gastrointestinal Oncology, University College London Hospital National Health Service Foundation Trust, London, United Kingdom.
  • Spencer J; School of Immunology and Microbial Sciences, King's College London, London, United Kingdom. Electronic address: jo.spencer@kcl.ac.uk.
  • Ciccarelli FD; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom. Electronic address: francesca.ciccarelli@crick.ac.uk.
Gastroenterology ; 161(4): 1179-1193, 2021 10.
Article em En | MEDLINE | ID: mdl-34197832
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Fenômenos Imunogenéticos / Microambiente Tumoral / Anticorpos Monoclonais Humanizados / Nivolumabe / Inibidores de Checkpoint Imunológico / Imunogenética Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Fenômenos Imunogenéticos / Microambiente Tumoral / Anticorpos Monoclonais Humanizados / Nivolumabe / Inibidores de Checkpoint Imunológico / Imunogenética Tipo de estudo: Clinical_trials / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article