Optimal regulation of tumour-associated neutrophils in cancer progression.

Abstract

In a tumour microenvironment, tumour-associated neutrophils could display two opposing differential phenotypes: anti-tumour (N1) and pro-tumour (N2) effector cells. Converting N2 to N1 neutrophils provides innovative therapies for cancer treatment. In this study, a mathematical model for N1-N2 dynamics describing the cancer survival and immune inhibition in response to TGF-β and IFN-β is considered. The effects of exogenous intervention of TGF-β inhibitor and IFN-β are examined in order to enhance N1 recruitment to combat tumour progression. Our approach employs optimal control theory to determine drug infusion protocols that could minimize tumour volume with least administration cost possible. Four optimal control scenarios corresponding to different therapeutic strategies are explored, namely, TGF-β inhibitor control only, IFN-β control only, concomitant TGF-β inhibitor and IFN-β controls, and alternating TGF-β inhibitor and IFN-β controls. For each scheme, different initial conditions are varied to depict different pathophysiological condition of a cancer patient, leading to adaptive treatment schedule. TGF-β inhibitor and IFN-β drug dosages, total drug amount, infusion times and relative cost of drug administrations are obtained under various circumstances. The control strategies achieved could guide in designing individualized therapeutic protocols.