The Landscape And Prognostic Value Of Immune Cells Infiltrating In Prostate Cancer

BackgroundProstate cancer(PCa)is one of the highest incidence cancers in men in the world.The main treatment for PCa are radical prostatectomy and androgen stripping therapy.However,those treatment may lead to hormone resistance and distant metastasis in patients,so the treatment options are limited.Immunotherapy has a good treatment outcome in many kinds of tumors.However,PCa patients have low sensitivity to immunotherapy and poor immunotherapy effects.Many studies have proved that tumor infiltrating immune cells(TIICs)are closely related to the survival and treatment of human cancer types and immunotherapy response.However,there is no systematic research on the immune cells infiltrating into the prostate cancer tissues.The mechanism of cell infiltration is not yet clear,and whether infiltrating immune cells can be used as therapeutic targets and prognostic evaluation indicators remain unknown.ObjectiveThis study aims to investigate the infiltration pattern of immune cells in the prostate cancer microenvironment and quantitatively analyze the content of 22 immune cells in the prostate cancer microenvironment,then to clarify the possible mechanisms affecting immune cell infiltration and evaluate specific infiltrating immune cells as potential prognostic biomarkers.Methods1.CIBERSORT deconvolution algorithm was used to extract the infiltration proportion of 22 immune cells from the standardized data set,and divide the samples with CIBERSORT p<0.05 into the normal group or the tumor group.2.T test was used to analyze the difference in the amount of infiltration of 22 immune cells between normal tissues and tumor tissues,and the correlation between the 22 immune cells and the pathological grade of prostate cancer was analyzed by Pearson correlation method.3.Calculation of the patient’s tumor mutation burden(Tumor Mutational Burden,TMB)score was based on single-nucleotide variant(SNV)data,and analyzed the relationship between TMB score and the amount of single immune cell infiltration.4.Univariate and multivariate regression was used to evaluate the impact of infiltrating immune cells on the prognosis of prostate cancer patients,and to evaluate its efficacy as a prognostic indicator.5.Chromatin immunoprecipitation(CHIP)experiment was used to screen transcription factors that cause abnormal activation of infiltrating NK cells.Results1.Difference analysis identified 10 kinds of immune cells with significant differences in the proportion of infiltration(7 immune cells were up-regulated on the prostate cancer microenvironment,and 3 immune cells were significantly reduced).2.The resting NK cells increased most,while the resting mast cell infiltration percentage decreased most in the prostate cancer microenvironment.3.The results of immunohistochemistry verified the accuracy of the CIBERSORT algorithm,with a coincidence rate of 0.672.4.The infiltration of five T cell subtypes were significantly related to the TMB score.The infiltration proportion of CD4+memory T cells,CD8+T cells,γδ T cells,and follicular helper T cells increases with the increase of TMB,and the infiltration proportion of resting CD4+memory T cells was negatively correlated with TMB.5.The genes mutations of S100A2,NOX1,AMH,BIRC5,AGTR1 significantly affected the infiltration of immune cells.6.A prediction model for prostate cancer patients based on 10 differently infiltrated immune cells(multivariate nomogram model)was constructed.The area under the curve(AUC)for the 5-year and 10-year survival predictions of prostate cancer patients,respectively reaching 0.796 and 0.862,which proved that the model has good predictive performance.7.The transcription factor MAX expressed by prostate cancer cells is related to multiple NK cell ligands expression of prostate cancer cells.The expression of MAX might affect the activation of NK cells in the prostate cancer microenvironment.ConclusionImmune cells that infiltrating into the prostate cancer microenvironment,especially infiltrating M1 macrophages and neutrophils,are closely related to the prognosis of patients,suggesting that these two types of immune cells may be potential targets for the diagnosis and treatment of prostate cancer.A nomogram model based on the amount of immune cell infiltration in the prostate cancer microenvironment can be used as one of the reference indicators for patient prognosis assessment.The low expression of MAX transcription factor in prostate cancer cells leads to abnormal activation of NK cells,which may be one of the reasons for the failure of immunotherapy.