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.
