Modeling CTL-mediated Tumor Cell Death Mechanisms and the Activity of Immune Checkpoints in Immunotherapy

Yixuan Wang

University of Michigan

"Modeling CTL-mediated Tumor Cell Death Mechanisms and the Activity of Immune Checkpoints in Immunotherapy"

Immunotherapy has dramatically transformed the cancer treatment landscape. Of the variety of types of immunotherapies available, immune checkpoint inhibitors (ICIs) have gained the spotlight. Although ICIs have shown promising results for some patients, the low response rates in many cancers highlight the challenges of using immune checkpoint blockade as an effective treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms. The first process is fast-acting and perforin/granzyme-mediated, and the second is a slower, Fas ligand (FasL)-driven killing mechanism. There is also evidence suggesting that the preferred killing mechanism by CTLs depends on the antigenicity of tumor cells. To determine the key factors affecting responses to checkpoint blockade therapy, we constructed an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD- L1 immune checkpoint. Specifically, we analyzed which aspects of the tumor-immune landscape affect the response to ICIs with endpoints of tumor size and composition in the short and long term. By generating a virtual cohort with heterogeneous tumor and immune attributes, we also simulated the therapeutic outcomes of immune checkpoint blockade in a largely diverse population. In this way, we identified key tumor and immune characteristics that are associated with tumor elimination, dormancy and escape. Our analysis sheds light on which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy.
Additional authors: Daniel Bergman; Erica Trujillo; Alexander T. Pearson; Randy Sweis; Trachette L. Jackson

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