Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms

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Project Summary/Abstract Recent strategies to stimulate anti-cancer immune responses have transformed treatment options for many cancer patients, but are critically hindered by the low abundance and/or suppression of lymphocytes in the tumor microenvironment of many cancers. This work aims to address this significant problem in the context of small cell lung cancer (SCLC), which has among the worst prognoses among all cancers and for which adaptive immune checkpoint inhibitors have shown limited success in improving patient outcomes. Strategies to stimulate macrophage activity are increasingly being investigated, as macrophages constitute a high percentage of total tumor cell mass in SCLC and many other cancers. Therapeutic monoclonal antibodies (mAbs) can induce macrophages to both kill cancer cells via phagocytosis and to prime adaptive immune responses. However, anti-phagocytic factors expressed by cancer cells, only some of which have been identified, enable resistance to phagocytosis. My long-term goal is to advance our fundamental knowledge of the mechanisms by which cancer cells evade antibody-dependent phagocytosis, which might create new therapeutic avenues to enhance mAb efficacy. I will build on an innovative CRISPR/Cas9-screening approach I have developed to identify factors that modulate cancer sensitivity to phagocytosis. This approach revealed a suite of known and novel anti-phagocytic pathways. The objective of this proposal is to investigate one of the most potent novel mechanisms I identified, and to test the central hypothesis that cancer cells metabolize inflammatory lipids to avoid activating macrophages. In Aim 1, I will undertake a series of in vitro experiments to understand the mechanistic basis of macrophage regulation by cancer-derived immunostimulatory lipids. In Aim 2, I will determine how cancer lipid regulation affects innate and adaptive anti-cancer immune responses using an immunocompetent mouse model for SCLC. Finally, in Aim 3, I will systematically characterize synergies between diverse anti-phagocytic pathways in SCLC to reveal how lipid regulators and other factors cooperate to block macrophage attack, which may suggest possible new combination therapeutic strategies. The expected outcome of these related but independent aims is an understanding of the molecular mechanisms of a novel immunosuppressive lipid metabolism pathway used by diverse cancers, including SCLC, to evade mAb therapies. These aims will be pursued within the stellar scientific environment of Stanford University, with research training and mentorship by an experienced team of experts in functional genomics, cancer immunology, lipid signaling, and bioinformatics. The career development plan involves research training in lipid analysis methods, mouse tumor models, and computational analysis of genetic screens, as well as professional training in communication, mentoring, and laboratory management, and will establish a strong foundation for my career as an independent investigator.