Therapy Induced Tumor Senescence Model

Abstract

Senescent cell accumulation and defective clearance of the senescent cells by the immune system occur with aging and increase the prevalence of diseases like cancer. Anti-tumor therapies can induce senescence in the tumor cells. Senescence Associated Secretory Phenotypes (SASP) secretion by these senescent tumor cells activates the innate NK cells which can detect and eliminate them. Mechanisms are unclear about how does it occur? A combination of immunotherapy and senotherapy has shown the possibility to reduce the tumor burden and increase the health span. The temporal and intensity dynamics of the therapeutic dose regimen remains to be studied. Therefore, a simplified therapy-induced senescence (TIS) phenomenological model is proposed to explain the mechanism of senescent tumor cell clearance by the NK immune cells and understand the possibility of a two-punch therapy technique in regulating tumors. Interaction strength changes for the cellular population within a healthy and an aged tumor microenvironment. The simulation result shows an oscillatory behavior existing between the tumor and immune cells. Tumor heterogeneity acts as inherent noise in sustaining the tumor for relapse emergence despite therapeutic clearance. The model indicates the formation of a robust oscillatory loop between the tumor, immune, and senescence cells which they can tune by modifying the phenotypic fitness landscape through secreted factors making them resistant despite selective removal of the sensitive populations by various therapies. The model highlights the importance of modified and aged tumor microenvironment by senescence tumor cells in obstructing clearance of both senescence and tumor cells by the innate immune system. Cancer therapies along with senolytics may have a robust and effective regulatory potential over tumor and senescence cells. The model also provides a preliminary analysis of the therapy temporal and intensity dosage regimen causing a therapeutic shift in tumors.