FOXA1 loss-of-function induces inflammatory cytokine signaling and immune suppression in prostate cancer

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancer death in American males. Androgen deprivation therapies extend patient lifespan, but can result in progression to castration resistant prostate cancer (CRPC). Moreover, treatment with next generation antiandrogens often results in further resistance and differentiation to neuroendocrine prostate cancer. Recently, immunotherapies, such as immune checkpoint inhibitors, have become an area of much interest. However, CRPC has shown a poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. Thus, we need a better understanding of how genetic alterations commonly seen in advanced PCa shape the tumor immune microenvironment (TIME), in order to inform the design of better-targeted immunotherapeutic approaches. We here propose to investigate the role of epithelial transcription factor Forkhead Box A1 (FOXA1) in regulating the TIME in PCa. FOXA1 is found to be downregulated in CRPC, and is among the most highly mutated genes in PCa. In accordance, we have previously shown that FOXA1 loss or mutation induces epithelial-mesenchymal transition and metastasis. However, whether FOXA1 loss-of-function induces an immunosuppressive TIME in PCa remains poorly understood. In preliminary studies, we noticed that inflammatory cytokines, such as CCL2, TGFB3, and IL8, which are associated with recruitment of immunosuppressive myeloid derived suppressor cells and tumor-associated macrophages, were among the most highly upregulated genes upon FOXA1 depletion or mutation. In our investigation of the mechanism by which FOXA1 represses the expression of inflammatory cytokines, we identified ARID1A as a FOXA1 co-repressor. Notably, we found FOXA1 and ARID1A proteins interacted and exhibited extensive co-occupancy on the chromatin in PCa cells. Moreover, ARID1A repressed genes were also enriched for inflammatory pathways. Thus, we hypothesize that FOXA1 loss or mutation in PCa unleashes ARID1A and induces epigenetic reprogramming and inflammatory cytokine signaling, thereby promoting an immunosuppressive tumor microenvironment and PCa progression. We here propose to: (1) decipher the molecular mechanisms by which wild type and mutant FOXA1 regulate inflammatory cytokine signaling, and (2) determine the extent to which FOXA1 loss or mutation induces an immunosuppressive tumor microenvironment in PCa.