Molecular and Immune Correlates of Lymphocyte Activation Gene-3 Expression in Renal Cell Carcinoma

BACKGROUND: Lymphocyte Activation Gene-3 (LAG-3) is an immune checkpoint receptor that has emerged as a biomarker of interest but its relationship with outcomes in renal cell carcinoma (RCC) is poorly characterized. This study evaluates molecular and immune correlates of LAG-3 expression and its association with outcomes. METHODS: De-identified DNA-NGS data (xT) and RNA-NGS (xR) from patients (pts) with RCC (n = 566) within the Tempus multi-modal database were analyzed using Lens. Eligible pts had first-line (1L) immunotherapy (IO) and biopsies collected within 1 year of IO. Samples were stratified into four quartiles by LAG-3 RNA expression (TPM). Immune cell proportions were estimated from RNA (quanTIseq). Real-world objective response rate (rwORR) was assessed within 90-days of IO. Real-world overall survival (rwOS), defined as time from 1L IO start to death, lost to follow-up, or 5 years after 1L, was analyzed using Cox proportional hazard models and p-values (Wald test). RESULTS: The median age was 61 and majority were male (72%), white (79%), with metastases at specimen collection (94%). BAP1 (p = 0.008) and NF2 (p = 0.015) were increased in the highest LAG-3 groups, while VHL, PBMR1, and SETD2 were not. LAG-3 correlated with higher CTLA4, PD1, PD-L1, PD-2, TIM3, and TIGIT RNA expression (all p < 0.001), and increased M1/M2 macrophages, NK, B, CD8 T, and Treg cell % (all p < 0.001). Higher LAG-3 expression was associated with improved rwORR and lower disease progression (p = 0.039). rwOS was not statistically significant (p = 0.2). CONCLUSIONS: LAG-3 is associated with distinct tumor immune features and may serve as a biomarker for early IO response in RCC.