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

We sought to validate levels of CD8⁺ 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). Tumor tissues (nivo: <i>n</i> = 116, evero: <i>n</i> = 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). 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%, <i>P</i> = 0.01) and DRR (33.3% vs. 14.1%, <i>P</i> = 0.03) and longer median PFS (9.6 vs. 3.7 months, <i>P</i> = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways (<i>q</i> < 0.1) and immune-related gene signature scores (<i>q</i> < 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. <i>ERVE-4</i> expression was associated with increased DRR and longer PFS in nivo-treated patients. High levels of CD8⁺ TIC expressing PD-1 but not TIM-3 and LAG-3 and <i>ERVE-4</i> 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.