The Regulatory Effect Of Interleukin-9(IL-9) Positive Immune Cells On The Immune Microenvironment Of Endometrial Carcinoma

Background:Interleukin-9(IL-9)is functionally active in immune modulation and pro-inflammatory function and is required for the pathogenesis of endometrial cancer(EC),especially endometrioid EC(EEC).The study aims to identify the sub-cluster of IL-9+immune cells,investigate the pleiotropic functions of IL-9+immunocytes,and establish an optimized prognostic nomogram for the precise treatment of EEC.Methods:This study included two cohorts of 1,417 patients with endometrial cancer.Cohort1 included 143 participants from the tertiary gynecology centers in Shanghai between 2013 and 2019.Cohort2 included 1,274 participants,which were collected from the TCGA and MSKCC datasets.ESTIMATE R package was used to calculate immune and stromal scores.Next,the TIMER platform was used to evaluate the tumor infiltration of immune cells.Metascape,Cytoscape,and GEPIA platforms were used for bioinformatic analysis.All statistical tests were performed using IBM SPSS Statistics(version 24;SPSS,Inc.Chicago,IL),Graph Pad Prism(version 8.0),and R(version 3.6.1).All tests were two-tailed;P<0.05 was considered statistically significant.Results:By using the ESTIMATE algorithm,immune and stromal scores were calculated,then immune and stromal-related genes were further identified;552 genes were elevated in the high immune score group and were selected for enrichment analysis.The correlation includes IFNγproduction,B cell activation,lymphocyte activation,and regulation of innate immune response.In cohort1,the mean age of patients at the time of diagnosis was 54±8.7 years.The mean size of the tumor was7.95 cm~2.High IL-9+lymphocyte infiltration was related to a better overall survival rate(OS,P=0.0027).Most IL-9+cell included ILC2s,Vδ2+γδT cells,and Th9 cells.To predict the OS of patients with EC,a prognostic nomogram was established.Each factor in the nomogram,including FIGO stage,IL-9 score,Vδ2+γδT cell infiltration,classification of differentiation,etc.,was assigned a weighted number of points,and the sum of points for each patient was in accordance with a specific predicted 3-,5-and10-year OS.IL-9/IL-9R axis played a vital role in EEC,the sub-cluster of IL-9R positive cells were also studied,and the associated function was analyzed.Additionally,PR(Progesterone Receptor,or PGR)expression was relevant to a higher density of IL-9+lymphocyte infiltration.However,PGRMC1(Progesterone Receptor Membrane Component 1)was negatively relevant to IL-9R(P=4.26e-8).Conclusion:There was a significant infiltration of IL-9+cells in tissue specimens of patients in EC cases,so as the overrepresentation of IL-9R.Additionally,our study established a prognostic nomogram to accurately predict individualized survival probability in EEC.Furthermore,the landscape of IL-9 producing cells in EC immunity was identified and could help us know more about the IL-9/IL-9R axis.