Tumor Immunometabolism Characterization In Ovarian Cancer With Prognostic And Therapeutic Implications

BackgroundOvarian cancer is a common cause of death related to gynecological cancer with 5-year survival rate less than 50%.Although improvements in the treatment of ovarian cancer reduced the mortality,70%of patients will experience a recurrence within three years after first-line treatment.Immunotherapy,especially immune checkpoint blockade therapy,is one of the most remarkable developments in the field of tumor therapy in recent years.Focusing on the tumor microenvironment may provide new treatment strategies for improving immune therapy efficacy.Metabolic disorders in tumor microenvironment have an important role on immune infiltration and immune response.Tumor metabolic reprogramming,such as glycolysis and glutamine metabolism,can affect the differentiation of T lymphocytes and the phenotype of macrophages.Therefore,clarifying the characteristics of immunometabolism of ovarian cancer and exploring the interaction of immunity and metabolism will provide a theoretical basis for discovering prognostic markers and guiding the treatment of ovarian cancer.Antigen presentation is a key step in anti-tumor immune cycle.However,it is often impaired in ovarian cancer.The reason for the impairment of tumor antigen presentation includes lack of tumor antigen,decreased antigen presentation cells and low or no expression of MHC molecules etc.It was found that competition of metabolic nutrients and the stimulation of metabolites have a widely impact on multiple steps of antigen presentation.Exploring the key factors affecting antigen presentation under the interaction of immunometabolism interaction could provide new ideas for improving the treatment efficacy in ovarian cancer.Methods and ResultsWe found immune genes(N=73)and metabolic genes(N=97)has prognostic significance in ovarian cancer.Based on it,we constructed an immunometabolism gene set(N=170),performed consensus clustering in ovarian cancer cohort and identified three immunometabolism subtypes with significant differences.Subtype 1,the "immune suppressive-glycan metabolism subtype",featured high levels of immunosuppressive cell infiltration and glycan metabolism activation;Subtype 2,the "immune inflamed-amino acid metabolism subtype",showed abundant adaptive immune cell infiltration and amino acid metabolism activation;Subtype 3,the"immune desert-endocrine subtype",was characterized by low immune cell infiltration and upregulation of hormone biosynthesis.Furthermore,we explored the relationships between immune infiltration and metabolic reprogramming,we found that epinephrine biosynthesis displayed significantly negative correlations with MHC molecules and antigen presentation cells.Which suggest that activation of epinephrine biosynthesis may impair tumor antigen presentation,inhibit anti-tumor immune response,and subsequently affect the prognosis.To construct a simple prognostic signature,we built risk score and nomogram as prognostic signatures.ConclusionThis study identified three immunometabolism subtypes and found there were differences among three subtypes in immune infiltration and metabolism reprogramming.Based on the correlation analysis between immune infiltration and metabolism reprogramming,we found activation of epinephrine biosynthesis could suppress the antigen presentation and promote immune escape in ovarian cancer.Overall,we proposed immunometabolism subtypes,explored the crosstalk between immune infiltration and metabolism reprogramming,and provided new perspectives for understanding ovarian cancer microenvironment.