Expression of T-cell exhaustion molecules and human endogenous retroviruses as predictive biomarkers for response to nivolumab in metastatic clear cell renal cell carcinoma Journal Article


Authors: Ficial, M.; Jegede, O. A.; Sant'Angelo, M.; Hou, Y.; Flaifel, A.; Pignon, J. C.; Braun, D. A.; Wind-Rotolo, M.; Sticco-Ivins, M. A.; Catalano, P. J.; Freeman, G. J.; Sharpe, A. H.; Hodi, F. S.; Motzer, R. J.; Wu, C. J.; Atkins, M. B.; McDermott, D. F.; Shukla, S. A.; Choueiri, T. K.; Signoretti, S.
Article Title: Expression of T-cell exhaustion molecules and human endogenous retroviruses as predictive biomarkers for response to nivolumab in metastatic clear cell renal cell carcinoma
Abstract: Purpose: We sought to validate levels of CD8þ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025). Experimental Design: Tumor tissues (nivo: n 1⁄4 116, evero: n 1⁄4 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months). Results: In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, P 1⁄4 0.01) and DRR (33.3% vs. 14.1%, P 1⁄4 0.03) and longer median PFS (9.6 vs. 3.7 months, P 1⁄4 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways (q < 0.1) and immune-related gene signature scores (q < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. ERVE-4 expression was associated with increased DRR and longer PFS in nivo-treated patients. Conclusions: High levels of CD8þ TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE-4 expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings. © 2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 5
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-03-01
Start Page: 1371
End Page: 1380
Language: English
DOI: 10.1158/1078-0432.Ccr-20-3084
PROVIDER: scopus
PUBMED: 33219016
DOI/URL:
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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  1. Robert Motzer
    1044 Motzer