Arginase 2 Downregulation in High-Grade Prostate Adenocarcinoma and Its Spatial Inverse Association with Tumor-Infiltrating Lymphocytes

Kaharuddin, Arif Budiman; Cangara, Muhammad Husni; Miskad, Upik A; Wahid, Syarifuddin; Achmad, Djumadi; Nelwan, Berti Julian

doi:10.31557/APJCP.2026.27.7.2713

Arginase 2 Downregulation in High-Grade Prostate Adenocarcinoma and Its Spatial Inverse Association with Tumor-Infiltrating Lymphocytes

Document Type : Research Articles

Authors

¹ Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia.

² Anatomical Pathology Laboratory, Hasanuddin University Hospital, Indonesia.

³ Sentra Diagnostik Patologia Makassar, Makassar, Indonesia.

10.31557/APJCP.2026.27.7.2713

Abstract

Objective: The interaction between metabolic enzymes and the immune microenvironment in prostate cancer is still complex. This study aimed to examine the relationship between Arginase 2 (ARG2) expression and tumor-infiltrating lymphocytes (TILs) in prostate adenocarcinoma patients, as well as its correlation with histopathological grading, thereby elucidating immunometabolic mechanisms within the Indonesian patient population. Methods: This observational analytic study utilized a cross-sectional design, incorporating 105 formalin-fixed paraffin-embedded (FFPE) tissue blocks of prostate adenocarcinoma obtained from referral hospitals in Makassar, Indonesia. Immunohistochemistry was used to find out how much ARG2 was expressed, and digital image analysis (QuPath) was used to get an objective H-Score. According to the International Immuno-Oncology Biomarkers Working Group guidelines, the density of TILs was measured on H&E-stained slides. Statistical analyses encompassed Spearman’s rank correlation, the Kruskal-Wallis test, and the Wilcoxon Signed-Rank test for spatial analysis. Result: The study population was predominantly characterized by high-grade tumors, with 45.7% categorized as Grade Group V (Gleason Score 9–10). The digital quantification of ARG2 was validated by manual scoring (r = 0.768, p < 0.001). There was no statistically significant correlation between ARG2 expression and TILs density on a global scale (r = 0.048, p = 0.630). Nonetheless, paired spatial analysis indicated a significant local disparity; tumor regions infiltrated by TILs demonstrated substantially diminished ARG2 expression relative to adjacent non-infiltrated regions (p = 0.009). Moreover, ARG2 expression exhibited a significant inverse correlation with WHO Grade Group (p < 0.001), indicating substantial downregulation in high-grade tumors. Conclusion: The expression of Arginase 2 is significantly reduced in high-grade prostate adenocarcinoma, signifying tumor dedifferentiation. Although ARG2 does not universally forecast immune infiltration, it influences the tumor microenvironment locally, with increased expression correlating with immune exclusion.

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