Mathematical modelling of natural killer (NK) cells recruitment in oncolytic virotheraphy

Abstract

Natural killer (NK) cells are known to constitute a major part of innate immunity against tumors and viral infections. Upon successfull viral entry into the tumor microenvironment (TME) or tumor, NK cells may however prematurely kill infected tumor cells and oncolytic viruses (OV), which then results in reduced overall e cacy of oncolytic virotherapy. In this thesis, we examine the e ects of NK cell recruitment within the TME during tumor treatment with OV. To achieve this, we devised and analyzed a simple mathematical model that describes the dynamic interactions of the tumor cells, OV and NK cells based on currently available preclinical and clinical literature. In particular, a central goal of this work is to investigate and characterize therapeutic conditions under which the synergistic balance between OV-induced NK responses and required viral cytopathicity may or may not result in a successful treatment. Interestingly, we found that NK cell recruitment to the TME must take place neither too early nor too late in the course of OV infection so that treatment will be successful. Notably, we also found that NK cell responses are most in uential at either early (partly because of rapid response of NK cells to viral infections or antigens) or later (partly because of antitumoral ability of NK cells) stages of oncolytic virotherapy. The model further predicts that: (a) an NK cell response augments oncolytic virotherapy only if viral cytopathicity is weak; (b) the recruitment of NK cells modulates tumor growth; and (c) the depletion of activated NK cells within the TME enhances the probability of tumor escape in oncolytic virotherapy. Taken together, our ndings demonstrate that OV infection is crucial, not just to cytoreduce tumor burden, but also to induce potent NK cell response necessary to achieve complete or at least partial tumor remission. Furthermore, our modeling framework supports combination therapies involving NK cells and OV which are currently used in oncolytic immunovirotherapy to treat several cancer types.