title: PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma.
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 ofPD-L1in a total of 335 STS cases. Copy number gains (CNG) were detected in 54 TCGA cases (21.1%), of which 21 (8.2%) harbored focalPD-L1CNG 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, includingJAK2. Patients withPD-L1CNG had higherPD-L1expression compared with STS without CNG (fold change, 1.8;p= 0.02), an effect that was most pronounced in the setting of focalPD-L1CNG (fold change, 3.0;p= 0.0027). STS withPD-L1CNG showed a significantly higher mutational load compared with tumors with a diploidPD-L1locus (median number of mutated genes; 58 vs. 40;p= 3.6E-06), andPD-L1CNG were associated with inferior survival (HR = 1.82;p= 0.025). In contrast, T-cell infiltrates quantified by mRNA expression ofCD3Zwere associated with improved survival (HR = 0.88;p= 0.024) and consequently influenced the prognostic power ofPD-L1CNG, with lowCD3Zlevels conferring poor survival in cases withPD-L1CNG (HR = 1.8;p= 0.049). These data demonstrate thatPD-L1GNG and elevated expression ofPD-L1occur 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.
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Institute of Pathology, Charité University Hospital , Berlin, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Disease (NCT) Heidelberg , Heidelberg, Germany.
authors.forename: Sadaf S
authors.identifier: 0000-0003-3468-8467
authors.initials: SS
authors.lastname: Mughal
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Priya
authors.identifier: 0000-0002-0754-4436
authors.initials: P
authors.lastname: Chudasama
authors.affiliation: Institute of Pathology, Charité University Hospital , Berlin, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-9249-4292
authors.initials: M
authors.lastname: Bockmayr
authors.affiliation: Institute of Pathology, Charité University Hospital , Berlin, Germany.
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lier
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Disease (NCT) Heidelberg, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.affiliation: German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
keywords: Amplification; CD274; PD-L1; immune checkpoint inhibition; soft-tissue sarcoma