PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma

• Verfasst von: Budczies, Jan [VerfasserIn]
• Verfasst von: Mechtersheimer, Gunhild [VerfasserIn]
• Verfasst von: Mughal, Sadaf Shabbir [VerfasserIn]
• Verfasst von: Chudasama, Priya [VerfasserIn]
• Verfasst von: Endris, Volker [VerfasserIn]
• Verfasst von: Lier, Amelie [VerfasserIn]
• Verfasst von: Lasitschka, Felix [VerfasserIn]
• Verfasst von: Penzel, Roland [VerfasserIn]
• Verfasst von: Brors, Benedikt [VerfasserIn]
• Verfasst von: Gröschel, Stefan [VerfasserIn]
• Verfasst von: Glimm, Hanno [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Renner, Marcus [VerfasserIn]
• Verfasst von: Fröhling, Stefan [VerfasserIn]
• Verfasst von: Stenzinger, Albrecht [VerfasserIn]
• Titel: PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma
• Verf.angabe: Jan Budczies, Gunhild Mechtersheimer, Carsten Denkert, Frederick Klauschen, Sadaf S. Mughal, Priya Chudasama, Michael Bockmayr, Korinna Jöhrens, Volker Endris, Amelie Lier, Felix Lasitschka, Roland Penzel, Manfred Dietel, Benedikt Brors, Stefan Gröschel, Hanno Glimm, Peter Schirmacher, Marcus Renner, Stefan Fröhling, and Albrecht Stenzinger
• E-Jahr: 2017
• Jahr: 07 Mar 2017
• Fussnoten: Gesehen am 24.08.2018
• Titel Quelle: Enthalten in: OncoImmunology
• Ort Quelle: Abingdon : Taylor & Franics, 2012
• Jahr Quelle: 2017
• Band/Heft Quelle: 6(2017,3) Artikel-Nummer e1279777, 9 Seiten
• ISSN Quelle: 2162-402X
• DOI: doi:10.1080/2162402X.2017.1279777
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Amplification
• Sach-SW: CD274
• Sach-SW: immune checkpoint inhibition
• Sach-SW: PD-L1
• Sach-SW: soft-tissue sarcoma
• K10plus-PPN: 1580367674

Abstract

Soft-tissue sarcomas (STS) are rare malignancies that account for 1% of adult cancers and comprise more than 50 entities. Current therapeutic options for advanced-stage STS are limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 signaling axis are being explored as new treatment modality in STS; however, the determinants of response to these agents are largely unknown. Using the sarcoma data set of The Cancer Genome Altas (TCGA) and an independent cohort of untreated high-grade STS, we analyzed DNA copy number status and mRNA expression of PD-L1 in a total of 335 STS cases. Copy number gains (CNG) were detected in 54 TCGA cases (21.1%), of which 21 (8.2%) harbored focal PD-L1 CNG and that were most prevalent in myxofibrosarcoma (35%) and undifferentiated pleomorphic sarcoma (34%). In the untreated high-grade STS cohort, we detected CNG in six cases (7.6%). Analysis of co-amplified genes identified a 5.6-Mb core region comprising 27 genes, including JAK2. Patients with PD-L1 CNG had higher PD-L1 expression compared with STS without CNG (fold change, 1.8; p = 0.02), an effect that was most pronounced in the setting of focal PD-L1 CNG (fold change, 3.0; p = 0.0027). STS with PD-L1 CNG showed a significantly higher mutational load compared with tumors with a diploid PD-L1 locus (median number of mutated genes; 58 vs. 40; p = 3.6E-06), and PD-L1 CNG were associated with inferior survival (HR = 1.82; p = 0.025). In contrast, T-cell infiltrates quantified by mRNA expression of CD3Z were associated with improved survival (HR = 0.88; p = 0.024) and consequently influenced the prognostic power of PD-L1 CNG, with low CD3Z levels conferring poor survival in cases with PD-L1 CNG (HR = 1.8; p = 0.049). These data demonstrate that PD-L1 GNG and elevated expression of PD-L1 occur in a substantial proportion of STS, have prognostic impact that is modulated by T-cell infiltrates, and thus warrant investigation as response predictors for immune checkpoint inhibition.