Obesity has been established as a risk factor in the development of a multitude of cancer types and causes substantial impairment of anti-tumor immunity. However, the underlying molecule mechanisms remain elusive. Our preliminary data demonstrated that a small nucleolar RNA (snoRNA),SNORD46,is upregulated in liver cancer and negatively correlates with the cytotoxic leukocytes infiltration. Genetic evidence indicated that the expression of SNORD46 leads to obesity and liver tumors resistant to immunotherapy. The goal of this proposal is to comprehensively characterize and implicate SNORD46 as a driver of obesity-associated liver cancer and demonstrate that targeting snoRNAs effectively improv...

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Obesity has been established as a risk factor in the development of a multitude of cancer types and causes substantial impairment of anti-tumor immunity. However, the underlying molecule mechanisms remain elusive. Our preliminary data demonstrated that a small nucleolar RNA (snoRNA),SNORD46,is upregulated in liver cancer and negatively correlates with the cytotoxic leukocytes infiltration. Genetic evidence indicated that the expression of SNORD46 leads to obesity and liver tumors resistant to immunotherapy. The goal of this proposal is to comprehensively characterize and implicate SNORD46 as a driver of obesity-associated liver cancer and demonstrate that targeting snoRNAs effectively improves the expansion and activation of CD8+ T-cells and NK cells and sensitizes obesity-associated liver cancer in immunotherapy. We will address our central hypothesis that snoRNAs act as essential gene targets that promote obesity and obesity-associated liver cancer initiation and immune resistance, which could be attenuated in vivo by an anti-sense oligonucleotide-based targeted therapy. First, we will define the underlying molecular mechanism of snoRNA-dependent immunoresistance. Then, we will determine how to prevent obesity-associated mammary gland tumors by targeting snoRNAs using obese mouse. Finally, we will determine that targeting snoRNAs sensitizes obesity-associated liver tumors to immune checkpoint inhibitors. The proposed study will provide initial genetic evidence for defining the crucial role of adipocyte-expressed snoRNAs in promoting obesity and obesity-associated liver cancer and elucidate the molecular mechanisms of the SNORD46-leukocyte interactions that drive obesity-associated liver cancer resistance to immunotherapy. We will delineate that targeting snoRNAs using locked nucleic acids (LNAs) effectively improves the proliferation/activation of CD8+ T-cells and NK cells in vivo, sensitizing obesity-associated liver cancer to immune checkpoint blockers.

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