IMAG/MSM WG Multiscale Modeling and Viral Pandemics Zoom

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Thursday January 23, 2025 at 3:00PM (EST)

Yi Jiang, Georgia State University will discuss: Immunogenic cell death: the key to unlocking the potential of combined immunotherapy and radiotherapy in cancer
In cancer treatment, immunogenic cell death (ICD) 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 enhancing the effectiveness of combined macrophage-based immunotherapy and radiotherapy for cancer treatment. Our model focuses on the  SIRPa-CD47 checkpoint and uses data from preclinical murine models of SIRPa-CD47 perturbation, with and without local irradiation. We find that radiotherapy invokes minimal ICD in tumors in wild-type mice and that ICD depends on radiation dose and tumor size in SIRPa-deficient mice. ICD levels are highest in SIRPa-deficient mice, followed by injection of SIRPa-deficient macrophages in wild-type mice, then treatments of anti-SIRPa, anti-CD47, and finally CD47-knockout. Analysis of the phagocytosis parameter reveals a descending order of phagocytic activity, from SIRPa-knockout, CD47-knockout, SIRPa-deficient macrophage injections, anti-SIRPa, anti-CD47, to wild-type macrophages that show no phagocytosis activity. Furthermore, the ICD and phagocytic activities together suggest a phenotypic span ranging from M1 to M2-like with the perturbations to the SIRPa-CD47 binding. 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.