Data-driven inference of regulators for cytokine-mediated tumor killing

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Project 1 Summary: Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig, https://cytosig.ccr.cancer.gov), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine, and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct immune cell populations in infectious diseases, chronic inflammation, and cancer using bulk and single-cell data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe COVID-19. Project 2 Summary: Despite recent breakthroughs in cancer immunotherapy, T-cell therapies achieve limited efficacy in solid tumors. Identifying regulators in T-cell dysfunction remains challenging due to limitations of current screening platforms. Using single-cell transcriptomic data from tumors as input, we developed a computational model to identify regulators of T-cell resilience, defined as the ability of T cells to proliferate under immune-suppressive signals such as TGF-beta and TRAIL. Integrating 14 single-cell transcriptomic cohorts from seven tumor types, we identified FIBP and TMEM222 as top regulators of T-cell resilience. Knocking out these genes, especially FIBP, in murine and human donor T cells significantly enhanced the efficacy of T-cell mediated cancer killing and adoptive cell therapy. We show that FIBP knockout in CD8 lymphocytes alleviates T-cell dysfunction by limiting cholesterol metabolisms, and high cholesterol level is known to inhibit T-cell activity. Together, our T-cell resilience model revealed FIBP as a candidate target to potentiate cancer immunotherapy.