Sunday, June 1, 2025
6/1/2025
Mechanisms of lmmunosuppression in MYCN-driven Neuroblastoma - PROJECT SUMMARY Enhanced MYCN activity drives the initiation, progression, and treatment resistance of multiple solid tumors, especially those arising from the brain, the spinal cord, or neural crest. Neuroblastoma, derived from the peripheral sympathetic ganglia, accounts for the second leading cause of deaths among children with solid tumors. Like many other solid tumors, MYCN-driven high-risk neuroblastoma harbors an immunosuppressive tumor microenvironment (TME), characterized by few cytotoxic lymphocytes and poor responses to immunotherapy. Despite intensive efforts, the mechanisms through which MYCN promotes an immunosuppressive TME remain incompletely understood and strategies to overcome this challenge are lacking. We recently reported that MYCN-driven neuroblastoma increases the secretion of CKLF1, a chemokine- like factor (CKLF) isoform, to recruit CD4+ cells to the TME, inducing immunosuppression and tumor aggressiveness. Analyses of primary neuroblastoma samples demonstrate a strong connection between MYCN, CKLF, and poor patient prognosis. The zebrafish model of MYCN-driven neuroblastoma simulates the immune system and tumor development in children and resembles human high-risk disease. Overexpression of cklf in the zebrafish neural crest attracts multiple immune cells, including CD4+ cells, to the TME as early as the premalignant stage, which incites immunosuppression while promoting tumor initiation and metastatic spread. On the other hand, depleting Cklf significantly inhibited MYCN-driven neuroblastoma initiation and progression while reverting the pro-TME to an immunogenic one. We and others found that CKLF1 binds to CC chemokine receptor 4 (CCR4), a cell surface receptor on CD4+ cells (e.g., Treg cells and macrophages). The above evidence formulates our hypothesis: CKLF1 secreted by MYCN-driven tumor cells recruits and exploits immune cells, particularly CD4+ cells, to induce an immunosuppressive TME and promote tumor aggressiveness, thus representing a novel immunotherapeutic target. We will leverage the unique imaging and genetic capacities of the zebrafish neuroblastoma model together with analyses of patient samples, in vitro co-culture systems, and murine models to pursue three complementary yet integrated aims. In Aim 1, we will characterize the types and properties of immune cells that CKLF1 recruits to the TME of MYCN-driven neuroblastoma. Experiments proposed in Aim 2 will elucidate the mechanisms by which CKLF1 recruits and modulates CD4+ cells to induce immunosuppression. In Aim 3, we will investigate the ability of inhibiting tumor-secreted CKLF1 to alleviate immunosuppression and thus enhance immunotherapy responses. Our team’s combined expertise in MYC/MYCN-driven neuroblastoma, tumor immunology, and single-cell transcriptomics technology is ideal for the proposed research. Due to the wide involvement of MYCN in human cancers, information gathered from our in-depth mechanistic studies and therapeutic strategy evaluation has the potential to apply to tumors beyond neuroblastoma, for improved responses to immunotherapy.
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