The impact of CDCA5 expression on the immune microenvironment and its potential utility as a biomarker for PD-L1/PD-1 inhibitors in lung adenocarcinoma

Background: Studies have highlighted the important role of cell division cycle associated 5 (CDCA5) in tumor-associated immune dysfunction. We studied immune dysfunction based on CDCA5 expression in lung adenocarcinoma and investigated its potential as a biomarker for patients undergoing anti-programmed death protein-1/ programmed death ligand-1 (PD-1/PD-L1) inhibitor therapy. Methods: We used the CIBERSORTx algorithm to investigate the immune cell distribution based on CDCA5 and explored its potential as a biomarker for PD-1/PD-L1 therapy using Tumor Immune Dysfunction and Exclusion in three lung adenocarcinoma datasets. Thus, we validated the role of CDCA5 as a biomarker in patients treated with PD-1/PD-L1 inhibitors. We also investigated the pathways through which CDCA5 regulates PD-L1 expression in a cell line. Results: The high CDCA5 expression group showed elevated interferon gamma signature, CD274 expression, CD8+ T cell levels, tumor mutation burden, and microsatellite instability. Higher CDCA5 expression was associated with poorer prognosis in patients not treated with PD-1/PD-L1 inhibitors. However, in patients treated with PD-1/PD-L1 inhibitors, higher CDCA5 expression correlated with better response rates and prognosis. CDCA5 expression positively correlated with inhibitory immune checkpoint molecules. CDCA5 regulated the expression of PD-L1 through the ANXA/AKT pathway, and combined suppression of CDCA5 and PD-L1 synergistically inhibited cell proliferation. Conclusions: CDCA5 served as a promising biomarker for patients undergoing PD-L1/PD-1 inhibitor treatment, and co-inhibition of CDCA5 and PD-L1 could serve as an effective therapeutic strategy.