High Immunoexpression of COX-2 as a Metastatic Risk Factor in ccRCC without PD-L1 Involvement

Abstract

Introduction Clear cell renal cell carcinoma (ccRCC) is the most lethal type of malignancy of the urinary tract system as it is resistant to chemotherapy and radiation and has a survival rate of less than 5% in cases of metastasis. Inflammation plays an essential role in the metastasis of ccRCC. Cyclooxygenase-2 (COX-2) is an inflammatory protein that affects the processes of carcinogenesis, invasion, migration, metastasis, and angiogenesis. COX-2 can modulate programmed death ligand-1 (PD-L1) expression and play a role in immune evasion, meaning that tumor cells are able to escape the body’s immune response and more easily metastasize. Purpose This study aims to determine the role of COX-2 and PD-L1 in the occurrence of ccRCC metastases. Materials and Methods This study is an observational analytical study, which employed a cross-sectional approach to examine the paraffin block samples of 40 ccRCC cases from Dr. Hasan Sadikin Hospital Bandung, Indonesia, between 2014 and 2021. Immunoexpression was measured using immunohistochemical staining for COX-2 in tumor cells and for PD-L1 in immune cells. PD-L1 calculation was measured using Qupath 0.2.3. digital software. Metastatic data were obtained using radiological imaging and pathological examinations. Meanwhile, the data were analyzed using the chi-square test for COX-2 and Fischer’s exact test for PD-L1. Results The research results revealed a significant association between COX-2 and the occurrence of metastases in ccRCC (p=0.001) with a prevalence odds ratio of 10.28. Positive PD-L1 immunoexpression of the immune cells (≥1%) was found in 14% (3/21) of the metastatic group and 5% (1/19) of the non-metastatic group (p=0.607). There was no association between COX-2 and PD-L1 immunoexpression (p=0.278). Conclusion This study shows that metastases in ccRCC patients are ten times as likely to be associated with high COX-2 immunoexpression than low COX-2 immunoexpression. COX-2 plays a role in the process of ccRCC metastasis without PD-L1 involvement.

Flavonoids with Anti-Angiogenesis Function in Cancer

“…The main pro-angiogenic activity of COX-2 occursviathe action of three ARA metabolites: PGI2, TXA2, and PGE2 [232]. Three eicosanoid products have a pivotal significance in downstream proangiogenic activities such as VEGF production, facilitation of blood vessel sprouting, migration, and tube development [233], improved endothelial cell survival via activating Akt production and increasing Bcl-2 level [234], stimulation of MMPs, initiation of EGFR-driven angiogenesis, and inhibition of interleukin-12 generation [235]. Compounds 4, 11, 19, 21, 23, 32, 39 in Figure 4 mitigate COX-2 in different ways and exerting the effect of inhibiting tumor neovascularization.…”