Expression of T-cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma.
2020
PURPOSE We sought to validate levels of CD8+ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker) (Pignon et al, 2019) and to investigate human endogenous retroviruses (hERVs) 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=116, evero: n=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 CR or PR 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=0.01) and DRR (33.3% vs 14.1%, p=0.03) and longer median PFS (9.6 vs 3.7 months, p=0.03) than low-IF biomarker patients. By RNA-seq, 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. ERVE4 expression was associated with increased DRR and longer PFS in nivo-treated patients. CONCLUSION High levels of CD8+ TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE4 expression predicted response to nivo (but not to evero) in mccRCC patients. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
32
References
10
Citations
NaN
KQI