Coexpression of lymphocyte-activation gene 3 and programmed death ligand-1 in tumor infiltrating immune cells predicts worse outcome in renal cell carcinoma

• Published in: International journal of immunopathology and pharmacology 2022-09, Vol.36, p.3946320221125588-3946320221125588
• Main Authors: Lee, Chan Ho, Jung, Soo Jin, Seo, Won Ik, Chung, Jae Il, Lee, Dae Sim, Jeong, Dae Hoon, Jeon, Youkyoung, Choi, Inhak
• Format: Article
• Language: English
• Subjects: Apoptosis; CD223 antigen; Cell activation; Cell death; Clear cell-type renal cell carcinoma; Data analysis; DNA microarrays; Genomes; Immune checkpoint; Immunohistochemistry; Kidney cancer; Ligands; Lymphocytes; Metastases; Multivariate analysis; Original; Patients; PD-L1 protein; Tumor-infiltrating lymphocytes
• ISSN: 0394-6320; 2058-7384
• DOI: 10.1177/03946320221125588

Objectives Lymphocyte-activation gene 3 (LAG-3) represents a potential immune checkpoint target for cancer treatment. We investigated LAG-3 expression and its prognostic value in patients with surgically treated clear cell renal cell carcinoma (RCC) and correlated LAG-3 expression with programmed cell death ligand 1(PD-L1). Methods We evaluated LAG-3 and PD-L1 expression using immunohistochemistry on tissue microarrays incorporating 134 primary excision specimens of clear cell RCC (ccRCC). The patients were analyzed as two groups: the whole cohort and those with metastatic RCC (mRCC). The cancer genome atlas (TCGA) data analysis of LAG-3 was done through UALCAN web servers. Results Using the UALCAN cancer transcriptional data analysis, we found that LAG-3 was overexpressed in ccRCC. LAG-3 expression was significantly correlated with PD-L1 expression in the whole cohort and in the mRCC group (all, p < 0.05). Both LAG-3⁺ RCC and PD-L1⁺ RCC presented with a higher TNM stage and higher Fuhrman nuclear grade (all, p < 0.05). PD-L1⁺/LAG-3⁺ RCC and PD-L1⁻/LAG-3⁺ RCC showed poorer cancer-specific survival (CSS) than PD-L1⁻/LAG-3⁻ RCC (all, p = 0.01). Similarly, PD-L1⁺/LAG-3⁺ mRCC and PD-L1⁻/LAG-3⁺ mRCC showed poorer CSS than PD-L1⁻/LAG-3⁻ mRCC (all, p < 0.05). Multivariate analysis showed that PD-L1⁺/LAG-3⁺ mRCC (hazard ratio: 3.19; 95% CI: 0.77–13.67; p = 0.033) was a predictor of poor CSS. Conclusion Both LAG-3⁺ and PD-L1⁺ RCC have adverse pathological features, and their coexpression predicts worse clinical outcomes. Our findings suggest LAG-3 blockade in combination with programmed cell death 1/PD-L1 blockade as a potential therapeutic approach for RCC.