Study On The Function Of Deubiquitinating Enzyme USP15 In Regulating Immune Infiltration Of Melanoma

Research background:Melanoma is a highly malignant tumor derived from melanocytes that occurs mostly in the skin and mucous membranes.It is a skin cancer with the highest fatality rate.With the increase of new cases and deaths every year,melanoma has become one of the fastest growing tumors.Unlike other cancers,it has high mutation rate and high ability to metastasize to blood,therefore early diagnosis and effective treatment are crucial.Surgical removal of diseased tissue dramatically improves cure rates for early-stage melanoma patients,while for late-stage patients,chemotherapy drugs are the most mainstream treatment.The immunotherapy and targeted drugs developed in the past decade have become the specific treatment methods for prolonging the survival period of advanced patients.USP15 is one of the largest subfamily members of deubiquitinase and has many important biological functions.Such as participating in regulating p53、TGF-βand NF-κB and other important signal transduction pathways are related to the progression of many cancers.In addition,USP15 has also been proved to participate in various reactions of the immune system,such as regulating the production of interferon and regulating T cell response.The latest research found that deubiquitination and activating the natural immune response of c GAS,which suggests the potential correlation between USP15 and immunotherapy.However,it is still unclear whether USP15 regulates the immune response and changes the immune microenvironment in melanoma.Methods and Results:In TCGA database,we found that the expression level of USP15 in melanoma was significantly lower than that in normal tissues.Metastatic melanoma patients with high expression of USP15 had better survival prognosis,and the immune pathway related to T cells was up-regulated,and there were significant correlations between the expression of USP15 and infiltration of multiple immune cell types.In vitro cytological experiments,we concluded that knockdown of USP15 did not affect the growth of melanoma cells.However,knockdown of USP15 remarkably promoted tumor growth and substantially reduced CD3~+T cell infiltration in mouse tumorigenesis experiments.Our research clarified the regulatory function of USP15 on melanoma-infiltrating T cells,which provides a potential target for future immunotherapy.Conclusion:1.Melanoma patients have better prognosis when USP15 is highly expressed,and its immune-related pathways are upregulated.2.USP15 has a complex regulatory role in the proliferation of melanoma cells in vitro.3.Knockdown of USP15 enhanced the tumorigenicity of mouse melanoma and inhibited the infiltration of CD3~+T cells in a mouse melanoma xenograft model.