Clinical cancer research : an official journal of the American Association for Cancer Research · 2022
Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma.
СтатьяРандомизированное исследованиеПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Denize Thomas, Hou Yue, Pignon Jean-Christophe, Walton Emily, West Destiny J, Freeman Gordon J, Braun David A, Wu Catherine J, Gupta Saurabh, Motzer Robert J, Atkins Michael B, McDermott David, Choueiri Toni K, Shukla Sachet A, Signoretti Sabina
Аннотация
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 = 0.04) on nivolumab compared with everolimus.
CONCLUSIONS: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms are likely intertwined 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.
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 = 0.04) on nivolumab compared with everolimus.
CONCLUSIONS: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms are likely intertwined 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.