Systems biology analysis of vaccine-induced immunity to infectious diseases in cancer patients

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Infectious diseases constitute a significant threat to global health and caused more than 2 million deaths worldwide in 2019. While much of the research on infectious diseases focuses primarily on analyzing immunity in otherwise healthy individuals, patients with preexisting medical conditions like cancer often suffer most. Cancer and its treatments are associated with dysregulated immune systems, and cancer patients are highly susceptible to infections (e.g., influenza, SARS-CoV-2). Importantly, cancer patients often respond poorly to vaccination. The molecular and cellular mechanisms underlying immune dysregulation and poor immunity in cancer patients are manifold, variable among individual patients/conditions, and currently not well understood. An in-depth understanding of these mechanisms is essential to identifying novel strategies to prevent infectious diseases and developing individualized therapies. In this project, I will fill this knowledge gap and determine 1) how cancer manipulates the immune system to cause dysregulation and poor vaccine responses and 2) how vaccines, in turn, affect the dysregulated immune system in the long term. To achieve this goal, I will use a multi-omics systems biology approach and analyze blood samples from cancer patients collected before and after vaccination. My research exploits high-resolution immune profiling technologies, including mass cytometry, single-cell transcriptomics, and epigenomics analyses. I combine these experimental tools with machine learning-driven, integrated, multilevel data analysis and functional validation assays. Recently, I applied this approach successfully to determine immune dysregulation during SARS-CoV-2 infection in humans and to show that influenza vaccines provide broad, nonspecific protection against a range of viral pathogens via epigenomic mechanisms. The project proposed here will provide 1) actionable, immunological targets for effective vaccination in cancer patients, 2) biomarker candidates identifying patients at risk of poor vaccine response, and 3) insights into the lasting, nonspecific impact of vaccines on cancer patients' immune systems. These insights will inspire novel vaccines tailored to cancer patients and intervention strategies to restore effective immunity in patients with dysregulated immune systems. In the longer term, my vision is to develop synergistic approaches that boost immunity against pathogens and tumors by, for instance, optimizing the interplay between vaccines and cancer treatments. The Emmy Noether program's funding and support network will be essential in realizing this vision.