Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts

被引:103
作者
Bortolomeazzi, Michele [1 ,2 ]
Keddar, Mohamed Reda [1 ,2 ]
Montorsi, Lucia [1 ,2 ]
Acha-Sagredo, Amelia [1 ,2 ]
Benedetti, Lorena [1 ,2 ]
Temelkovski, Damjan [1 ,2 ]
Choi, Subin [1 ,2 ]
Petrov, Nedyalko [3 ]
Todd, Katrina [3 ]
Wai, Patty [4 ]
Kohl, Johannes [4 ]
Denner, Tamara [5 ]
Nye, Emma [5 ]
Goldstone, Robert [6 ]
Ward, Sophia [6 ]
Wilson, A. Gareth [7 ,8 ]
Al Bakir, Maise [7 ,8 ]
Swanton, Charles [7 ,8 ]
John, Susan [9 ]
Miles, James [10 ]
Larijani, Banafshe [10 ,11 ,12 ,13 ]
Kunene, Victoria [14 ]
Fontana, Elisa [15 ]
Arkenau, Hendrik-Tobias [15 ,16 ]
Parker, J. Peter [2 ,17 ]
Rodriguez-Justo, Manuel [18 ]
Shiu, Kai-Keen [19 ]
Spencer, Jo [9 ]
Ciccarelli, D. Francesca [1 ,2 ]
机构
[1] Francis Crick Inst, Canc Syst Biol Lab, London NW1 1AT, England
[2] Kings Coll London, Sch Canc & Pharmaceut Sci, London, England
[3] Guys & St Thomas Natl Hlth Serv Trust, Biomed Res Ctr, London, England
[4] Francis Crick Inst, State Dependent Neural Proc Lab, London, England
[5] Francis Crick Inst, Expt Histopathol, London, England
[6] Francis Crick Inst, Adv Sequencing Facil, London, England
[7] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England
[8] UCL, Canc Res UK Lung Canc Ctr Excellence, Canc Inst, London, England
[9] Kings Coll London, Sch Immunol & Microbial Sci, London SE1 9RT, England
[10] FASTBASE Solut SL, Derio, Spain
[11] Univ Basque Country, Basque Fdn Sci, Res Ctr Expt Marine Biol & Biotechnol Biophys Ins, Cell Biophys Lab,Ikerbasque, Leioa, Bizkaia, Spain
[12] Univ Bath, Dept Pharm & Pharmacol, Cell Biophys Lab, Ctr Therapeut Innovat, Bath, Avon, England
[13] Univ Bath, Dept Phys, Bath, Avon, England
[14] Univ Hosp Birmingham Natl Hlth Serv Fdn Trust, Med Oncol, Birmingham, W Midlands, England
[15] Sarah Cannon Res Inst UK, Drug Dev Unit, London, England
[16] Univ Coll Hosp, Dept Oncol, London, England
[17] Francis Crick Inst, Prot Phosphorylat Lab, London, England
[18] UCL, Dept Histopathol, Canc Inst, London, England
[19] Univ Coll London Hosp Natl Hlth Serv Fdn Trust, Dept Gastrointestinal Oncol, London, England
基金
欧盟地平线“2020”;
关键词
Anti-PD1; Immunotherapy; Tumor Mutational Burden; Wnt Signaling; Interferon Gamma; CD8 T cells; TUMOR MUTATIONAL BURDEN; COMPREHENSIVE ANALYSIS; IMMUNOTHERAPY;
D O I
10.1053/j.gastro.2021.06.064
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Colorectal cancer (CRC) shows vari-able 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) immuno-therapy. 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 co-horts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytom-etry, detection of programmed death-ligand 1 (PDL1) inter-action 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 acti-vation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and prolifer-ating PD1 thorn CD8 T cells interacting with PDL1 thorn 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 be-tween CD8 T cells and macrophages to promote cytotoxic antitumor activity.
引用
收藏
页码:1179 / 1193
页数:15
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