The oncologist · 2026
Molecular and immune correlates of lymphocyte activation gene-3 expression in renal cell carcinoma.
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Dudipala Harshitha, Dugan Adam J, Jariwala Unnati, Ronski Karyn, Mercer Jacob, Saad Eddy, Masri Jad El, Machaalani Marc, Saleh Mustafa, Layng Kayla Viets, Yu Yingying, Signoretti Sabina, Braun David, Pal Sumanta K, Choueiri Toni K, McKay Rana R
Аннотация
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 (1 L) immunotherapy (IO) and biopsies collected within 1 year of IO. Samples were stratified into 4 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 1 L IO start to death, lost to follow-up, or 5 years after 1 L, 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 = .008) and NF2 (P = .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 < .001), and increased M1/M2 macrophages, NK, B, CD8 T, and Treg cell % (all P < .001). Higher LAG-3 expression was associated with improved rwORR and lower disease progression (P = .039). rwOS was not statistically significant (P = .2).
CONCLUSIONS: LAG-3 is associated with distinct tumor immune features and may serve as a biomarker for early IO response in RCC.
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 (1 L) immunotherapy (IO) and biopsies collected within 1 year of IO. Samples were stratified into 4 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 1 L IO start to death, lost to follow-up, or 5 years after 1 L, 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 = .008) and NF2 (P = .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 < .001), and increased M1/M2 macrophages, NK, B, CD8 T, and Treg cell % (all P < .001). Higher LAG-3 expression was associated with improved rwORR and lower disease progression (P = .039). rwOS was not statistically significant (P = .2).
CONCLUSIONS: LAG-3 is associated with distinct tumor immune features and may serve as a biomarker for early IO response in RCC.