Model-based genotype-phenotype mapping used to investigate gene signatures of immune sensitivity and resistance in melanoma micrometastasis.
In this paper, we combine kinetic modelling and patient gene expression data analysis to elucidate biological mechanisms by which melanoma becomes resistant to the immune system and to immunotherapy. To this end, we systematically perturbed the parameters in a kinetic model and performed a mathematical analysis of their impact, thereby obtaining signatures associated with the emergence of phenotypes of melanoma immune sensitivity and resistance. Our phenotypic signatures were compared with published clinical data on pretreatment tumor gene expression in patients subjected to immunotherapy against metastatic melanoma. To this end, the differentially expressed genes were annotated with standard gene ontology terms and aggregated into metagenes. Our method sheds light on putative mechanisms by which melanoma may develop immunoresistance. Precisely, our results and the clinical data point to the existence of a signature of intermediate expression levels for genes related to antigen presentation that constitutes an intriguing resistance mechanism, whereby micrometastases are able to minimize the combined anti-tumor activity of complementary responses mediated by cytotoxic T cells and natural killer cells, respectively. Finally, we computationally explored the efficacy of cytokines used as low-dose co-adjuvants for the therapeutic anticancer vaccine to overcome tumor immunoresistance.
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Systems Biology and Mathematical Modelling Group, University of La Laguna, Spain.
Guido
G
Santos
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Institute of Mechanics, Bulgarian Academy of Science, Sofia, Bulgaria.|University of Transport, Sofia, Bulgaria.
Svetoslav
S
Nikolov
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Xin
X
Lai
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Martin
M
Eberhardt
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Florian S
FS
Dreyer
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Sushmita
S
Paul
Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Gerold
G
Schuler
Laboratory of Systems Tumor Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.|Department of Dermatology and Erlangen University Hospital and Faculty of Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Germany.
Julio
J
Vera
D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods*; D063990:Gene Ontology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D008962:Models, Theoretical; D061206:Neoplasm Micrometastasis / Q000235:genetics / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology