Article (Scientific journals)
In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer.
Kather, Jakob Nikolas; Poleszczuk, Jan; Suarez-Carmona, Meggy et al.
2017In Cancer Research, 77 (22), p. 6442-6452
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Keywords :
Colon/immunology/pathology; Colorectal Neoplasms/immunology/pathology/therapy; Computer Simulation; Humans; Immunologic Surveillance; Immunotherapy/methods; Lymphocytes/immunology/pathology; Models, Immunological; Outcome Assessment (Health Care); Prognosis; Rectum/immunology/pathology; Survival Analysis
Abstract :
[en] Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442-52. (c)2017 AACR.
Disciplines :
Oncology
Author, co-author :
Kather, Jakob Nikolas
Poleszczuk, Jan
Suarez-Carmona, Meggy ;  Université de Liège - ULiège
Krisam, Johannes
Charoentong, Pornpimol
Valous, Nektarios A.
Weis, Cleo-Aron
Tavernar, Luca
Leiss, Florian
Herpel, Esther
Klupp, Fee
Ulrich, Alexis
Schneider, Martin
Marx, Alexander
Jager, Dirk
Halama, Niels
More authors (6 more) Less
Language :
English
Title :
In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer.
Publication date :
2017
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
American Association for Cancer Research, United States - Maryland
Volume :
77
Issue :
22
Pages :
6442-6452
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c)2017 American Association for Cancer Research.
Available on ORBi :
since 11 January 2019

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