Abstract Summary/Description
Immunogenic cell death (ICD) in cancer treatment is triggered by irradiation or chemotherapy. It promotes the release of tumor-associated antigens, changes the tumor microenvironment, and activates the anti-tumor immune system response. Here, we develop a mathematical model to determine the role of ICD in combined, macrophage-based immunotherapy and radiotherapy, with a specific focus on the SIRPα-CD47 pathway. The model is calibrated using tumor growth in preclinical murine models of SIRPα perturbation, with and without local irradiation. The model first discovers that radiotherapy invokes minimal ICD in tumors in wild-type mice, and that ICD depends on radiation dose and tumor size in SIRPα-deficient mice. ICD levels are highest in SIRPα-deficient mice, followed by injection of SIRPα-deficient macrophages in wild-type mice, then treatments of anti-SIRPα, anti-CD47, and finally CD47-knockout. Analysis of the phagocytosis parameter reveals a descending order of phagocytic activity, from SIRPα-knockout, CD47-knockout, SIRPα-deficient macrophage injections, anti-SIRPα, anti-CD47, to wild-type macrophages that show no phagocytosis activity. The ICD and phagocytotic activities together suggest a phenotypic span ranging from M1 to M2-like with the perturbations to the SIRPα- CD47 pathway. Moreover, the model predicts the abscopal effect of the combined radio- and macrophage-based immuno- therapy. We further predict the treatment efficacy given radiation doses, macrophage phagocytosis capacity, and ICD strength, for various tumor sizes. These results highlight the critical role of ICD in capitulating the efficacy of the combined radio- and immuno-therapies and offer a new framework to better conceptualize and design optimal cancer treatment strategies.
