Coexpression of LAG-3 and PD-L1 in tumor infiltrating immune cells predicts worse outcome in clear cell renal cell carcinoma

Lymphocyte-activation gene 3 (LAG-3) protein is a potential immune checkpoint target for cancer treatment. Thus, we investigated LAG-3 expression and its prognostic value in clear cell renal cell carcinoma (ccRCC) and correlated LAG-3 expression with programmed cell death ligand 1 (PD-L1) using immunohistochemistry on tissue microarrays incorporating 134 ccRCC primary excision specimens. The study patients were analyzed as two groups: the whole cohort and those with metastatic renal cell carcinoma (mRCC). 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 in the whole cohort presented with a higher TNM stage and higher Fuhrman nuclear grade (all, p <  0.05). According to the International Metastatic Renal Cell Carcinoma Database Consortium risk classification, there were more intermediate- and poor-risk patients in both LAG-3⁺ mRCC and PD-L1⁺ mRCC than LAG-3⁻ mRCC and PD-L1⁻ mRCC (all, p <  0.05). PD-L1⁺/LAG-3⁺ RCC and PD-L1⁻/LAG-3⁺ RCC in the whole cohort 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; p  = 0.033) was a predictor of poor CSS. Our findings provided a scientific rationale for LAG-3 blockade in combination with programmed cell death 1/PD-L1 blockade as a potential therapeutic approach for RCC.