Cancer immunotherapy, specifically immune checkpoint blockade therapy, has been found to be effective in the treatment of metastatic cancers. However, only a subset of patients with certain cancer types achieve clinical responses. Consequently, elucidating immune system-related pre-treatment biomarkers that are predictive with respect to sustained clinical response is a major research priority. Another research priority is evaluating changes in the immune system before and after treatment in responders and non-responders. Specifically, our group has been studying immune signaling networks as an accurate reflection of the global immune state. Flow cytometry data (FACS, Fluorescence-activated cell sorting) characterizing immune signaling in peripheral blood mononuclear cells (PBMC) from gastroesophageal adenocarcinoma (GEA) patients were used to analyze changes in immune signaling networks in this setting. We developed a novel computational pipeline to perform secondary analyses of FACS data using systems biology / machine learning / information-theoretic techniques and concepts, primarily based on Bayesian network modeling. Application of this novel pipeline resulted in determination of immune markers, combinations / interactions thereof, and corresponding immune cell population types that are associated with clinical responses. Future studies are planned to generalize our analytical approach to different cancer types and corresponding datasets.
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Author SummaryIt is difficult to predict whether a cancer patient undergoing immunotherapy treatments will respond. As immunotherapy is expensive and may lead to autoimmune toxicities, patient selection is an important issue. One way to gain deeper insight into the underlying processes is to study changes in immune signaling networks during the treatment course. These networks can be modeled, visualized, and quantified using systems biology / machine learning methods, such as Bayesian networks (BNs). Here, we present a BN-based analytical strategy for devising and comparing immune signaling networks, and apply it to data obtained from patients in a gastrointestinal cancer immunotherapy clinical trial. We identify potentially predictive immune biomarkers, and compare and contrast the resulting network models in different groups of patients, before and after therapy. Our analytical strategy generalizes to different cancers and immunotherapy regimens.