Abstract
Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear. To explore the effects of ADT on PCa TIM, RNA sequencing was performed on six paired pre-ADT biopsy and post-ADT PCa lesions, and five paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa. Bioinformatics methods including ESTIMATE and ssGSEA were used to evaluate the stromal immune score and immune cell infiltration in PCa and paracancerous tissues. Weighted correlation network analysis was used to screen hub genes in the ADT-induced immune remodeling process. The results showed differences exist between PCa and paracancerous tissues in response to ADT. Compared with paracancerous tissues, the immune remodeling effect of ADT in PCa was more intense. ZFP36, JUNB, and SOCS3 served as hub genes in the ADT-induced immune remodeling process and were associated with PSA recurrent-free survival in the TCGA and our neoadjuvant ADT cohort. To investigate the joint action of the above three hub genes, an immune signature score was constructed. The results showed that immune signature score-based immune subtypes reveal the heterogeneity of the immune microenvironment of PCa and showed significant differences in patient prognosis, tumor immune infiltration, mutation burden, and landscape.
Highlights
Prostate cancer (PCa) is the most common cancer among men[1]
After removing the batch effect, the results showed that the infiltration levels of many immune cell types were increased in Androgen deprivation therapy (ADT) samples compared to the primary PCa samples but decreased in castration-resistant PCa (CRPC) samples
Few studies have comprehensively evaluated the effect of ADT therapy on tumor immune microenvironment (TIM) in PCa
Summary
PCa lesions and five paired paracancerous benign tissues from patients with locally advanced PCa (Supplementary Table S1). Pearson’s correlation analysis further confirmed that five hub genes were highly correlated with the majority of the infiltration level of 22 immune cell types in the immune microenvironment (Fig. 3e) We validated these five hub genes in the The Cancer Genome Atlas (TCGA) PCa cohort. Given the high correlation and significant impact on PSA RFS, a PCA-based variable, the immune signature score was calculated to compress the expression level of three hub genes (ZFP36, JUNB, and SOCS3). Kaplan–Meier curve analysis showed that high immunohistochemical activity levels of ZFP36, JUNB, and SOCS3 in radical prostatectomy PCa tissues were associated with favorable PSA RFS in our neoadjuvant ADT cohort (Fig. 4e). Signature 3 related to DNA double-strand break repair was higher in the immune-low subtype than in the immune-high subtype (Fig. 6d)
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