Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions.
Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
Center for Advancing Electronics, Technische Universität Dresden, 01062 Dresden, Germany Center for Information Services and High Performance Computing, Technische Universität Dresden, 01062 Dresden, Germany Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Center for Infectious Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany haralambos.hatzikirou@tu-dresden.de.
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Hatzikirou
Center for Advancing Electronics, Technische Universität Dresden, 01062 Dresden, Germany Center for Information Services and High Performance Computing, Technische Universität Dresden, 01062 Dresden, Germany.
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Alfonso
Molecular Immunology, Helmholtz Center for Infectious Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
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Mühle
Molecular Immunology, Helmholtz Center for Infectious Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
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Stern
Molecular Immunology, Helmholtz Center for Infectious Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany Institute of Immunology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
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Weiss
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Center for Infectious Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
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Meyer-Hermann
D000818:Animals; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy
immunomodulatory interventions; mathematical modelling; murine tumour growth experiments; tumour–immune system interactions; vascular normalization