PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma.
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.
['Budczies|Jan|J|', 'Mechtersheimer|Gunhild|G|', 'Denkert|Carsten|C|', 'Klauschen|Frederick|F|', 'Mughal|Sadaf S|SS|0000-0003-3468-8467', 'Chudasama|Priya|P|0000-0002-0754-4436', 'Bockmayr|Michael|M|0000-0002-9249-4292', 'Jöhrens|Korinna|K|', 'Endris|Volker|V|', 'Lier|Amelie|A|', 'Lasitschka|Felix|F|', 'Penzel|Roland|R|', 'Dietel|Manfred|M|', 'Brors|Benedikt|B|', 'Gröschel|Stefan|S|', 'Glimm|Hanno|H|', 'Schirmacher|Peter|P|', 'Renner|Marcus|M|', 'Fröhling|Stefan|S|', 'Stenzinger|Albrecht|A|']
PD-L1 CD274 soft-tissue sarcoma immune checkpoint inhibition Amplification