Mathematical Modelling of Tumour-Immune Interactions and Cancer Therapy

Mahasa, Khaphetsi Joseph (2017-12)

Thesis (PhD)--Stellenbosch University, 2017.

Thesis

ENGLISH ABSTRACT : The immune system plays a key role against the development and progression of tumor cells mainly because of its capability of recognizing and destroying cancerous cells. While incredible research efforts have been made over the past decades to decipher the complexity of the tumor-immnue interactions, there is still a lack of a definite and complete picture of these interactions. This may be attributed to the fact that tumor cells develop intricate mechanisms to evade detection and control by the immune system and resist treatments. Although this has been attributed to tumor escape from the immune system, no quantitative studies have been made to precisely characterize key tumor evasion mechanisms from immune surveillance. There is a growing need for new modeling approaches that take into account the complexity of immune system response and/or tumor escape mechanisms, and the recent advances in cancer therapy. This lack has motivated the work in this thesis. We focused our research on addressing the following three scientific questions: (1) How do tumors evolve by escaping immune surveillance? (2) How can oncolytic virus infection of some normal cells in the vicinity of tumor cells enhance oncolytic virotherapy? (3) How can the use of cell carriers for the delivery of oncolytic virus particles to tumor sites affect the outcomes of oncolytic virotherapy in the presence of active immune response? To address these major questions, we have devised three novel mathematical models to study the behaviour of tumor cells following their interactions with key cytotoxic immune cells and oncolytic viruses. The results herein this thesis show the development of immunoresistant phenotype by tumor cells to effectively evade the immune system. This thesis supports the natural killer (NK) cell-based immunotherapeutic approaches that are aimed at enhancing the immune surveillance of tumors. Our work also highlights an interesting possibility of infecting some normal cells in the vicinity of tumor cells to increase the oncolytic infectious titers within tumor microenvironment. Additionally, our findings provide pertinent information on how the use of certain cell carriers may enhance oncolytic virotherapy in the presence of effective immune response within the tumor microenvironment.

AFRIKAANSE OPSOMMING : Die immuunstelsel speel ’n sleutelrol om die ontwikkeling en groei van tumor selle teen te werk, hoofsaaklik as gevolg van die vermo¨e om kanker selle te herken en te vernietig. Terwyl ongelooflike navorsing oor die afgelope dekades gedoen is om die kompleksiteit van die tumor-immuun interaksies te ontleed, is daar nog nie ’n definitiewe en volledige beeld van hierdie interaksies nie. Dit kan toegeskryf word aan die feit dat tumorselle ingewikkelde meganismes ontwikkel om opsporing en beheer deur die immuunstelsel te ontduik en behandelings te weerstaan. Alhoewel dit toegeskryf word aan tumors wat van die immuunstelsel onsnap, is geen kwantitatiewe studies gedoen om die belangrikste ontduikingsmeganismes teen immuniteitswaarneming presies te karakteriseer nie. Daar is ’n toenemende behoefte aan nuwe modelleringsbenaderings wat die kompleksiteit van die immuunstelselrespons en / of tumor-ontsnappingsmeganismes in ag neem, asook die onlangse vordering in kankerterapie. Hierdie gebrek het die werk in hierdie proefskrif gemotiveer. Ons navorsing is gefokus daarop om die volgende drie vrae aan te spreek: (1) Hoe verander of ontwikkel die gewasse deur die immuunstelsel se toesig vry te spring? (2) Hoe kan onkolitiese virusinfeksie van sommige normale selle in die omtrek van tumor selle onkolitiese viroterapie verbeter? (3) Watter invloed kan die gebruik van seldraers vir die toediening van onkolitiese virusdeeltjies na die omgewing van die gewas h op die resultaat van onkolitiese virapie in die teenwoordigheid van aktiewe immuunrespons? Om hierdie hoofvrae aan te spreek, het ons drie wiskundige modelle opgestel om die gedrag van tumorselle te ondersoek deur hul interaksies met belangrike sitotoksiese immuunselle en onkolitiese virusse te volg. Die resultate in hierdie proefskrif toon die ontwikkeling van immunoresistante fenotipe deur tumorselle om die immuunstelsel doeltreffend te ontduik. Hierdie proefskrif ondersteun die natuurlike uitwisser (NK) se selgebaseerde immunoterapeutiese benaderings wat daarop gemik is om die immuunstelsel se opsporing van gewasse te verbeter. Ons werk beklemtoon ook die interessante moontlikheid om sommige normale selle in die omgewing van tumorselle te besmet om die onkolitiese infeksie tellings binne die mikro-omgewing van die tumor te verhoog. Daarbenewens verskaf ons bevindings relevante inligting oor hoe die gebruik van sekere seldraers onkolitiese viroterapie kan verbeter in die teenwoordigheid van effektiewe immuunrespons binne die gewas se mikro-omgewing.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/102597
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