PURPOSE: Our study examines tumor growth dynamics and immunosuppression under the presence of immune attack to identify optimal immune pulsing treatment strategies. BACKGROUND: TIL therapy is an emerging immunotherapy where activated T cells are injected into the patient. This therapy can fail due to tumor-induced immunosuppression, for example via the PDL1/PD1 axis. PDL1 expression has been studied and can increase under IFNg, released by activated T cells, but PD-L1 relaxation is not understood. We hypothesize that there may be better strategies of therapy delivery that maximize tumor kill while minimizing immune suppression. We investigate these complex PD-L1 driven dynamics through a unique combination of in vitro studies and mathematical modeling. METHODS: We have collected in vitro PD-L1 expression on NSCLC cells, which were either untreated or treated for 48 hours with high dose IFNg followed by chronic low dose IFNg for 21 days. To reinforce our in vitro findings, we developed a hybrid agent-based model (ABM). The agents in the ABM are tumor cells having variable PD-L1 expression, and immune cells that secrete IFNg and can kill tumor cells. Tumor cells can be randomly or cluster seeded. IFNg is modeled as either a binary well-mixed pulse (to simulate the in vitro experimental setup), or as a diffusible via a reaction-diffusion process (to simulate the tumor-immune cell interactions in an in vivo spatial manner). We model TIL therapy as an immune cell pulse, given at regular or irregular intervals and with different quantities of cells. RESULTS: Our ABM is calibrated to capture in vitro data dynamics. Under certain combinations of spatial configurations of the tumor and intermittent immune dosing schedules, we observe the presence of ‘sweet spots’ where tumor extinction is possible and immune exhaustion is avoided. This indicates that an appropriate pulsing of TIL therapy may lead to better overall immune efficacy than a bolus injection or continuous immunotherapy, by preventing sustained suppression that increases immune cell exhaustion, despite the potential for tumor regrowth between pulses. Our novel findings can potentially benefit clinical cancer research by giving multiple insights related to the tumor extinction, equilibrium and escape phenomena.