期刊
CLINICAL CANCER RESEARCH
卷 28, 期 18, 页码 4045-4055出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-22-0923
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类别
资金
- Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE [P50-CA101942-12]
- DOD CDMRP [W81XWH-18-1-0480, W81XWH-18-1-0366]
- Bristol Myers Squibb
- Dana-Farber/Harvard Cancer Center Kidney Program [P30 CA06516]
- George-town-Lombardi Comprehensive Cancer Center CCSG [P30 CA051008]
- William M. Scholl Foundation
- Kohlberg Chair at Harvard Medical School
- Trust Family
- Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute
- Memorial Sloan Kettering Cancer Center [P30 CA008748]
The study explores the molecular correlates of TC PD-L1 expression in ccRCC and its predictive role in anti-PD-1 monotherapy. The results show that TC PD-L1 expression is associated with overexpression of immune-and cell proliferation-related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. Additionally, a specific molecular RCC subtype enriched in TC PD-L1 positive tumors is found to have longer progression-free survival and higher objective response rate.
Purpose: PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy. Experimental Design: RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes. Results: In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune-and cell proliferation-related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune-and cell proliferation-related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13-0.83) and higher objective response rate (30% vs. 0%, P 1/4 0.04) on nivolumab compared with everolimus. Conclusions: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms are likely inter-twined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC.
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