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000120516 1001_ $$0P:(DE-HGF)0$$aBudczies, Jan$$b0$$eFirst author
000120516 245__ $$aPD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma.
000120516 260__ $$aAustin, Tex.$$bLandes Bioscience$$c2017
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000120516 520__ $$aSoft-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.
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000120516 7001_ $$aMechtersheimer, Gunhild$$b1
000120516 7001_ $$0P:(DE-HGF)0$$aDenkert, Carsten$$b2
000120516 7001_ $$aKlauschen, Frederick$$b3
000120516 7001_ $$00000-0003-3468-8467$$aMughal, Sadaf S$$b4
000120516 7001_ $$00000-0002-0754-4436$$aChudasama, Priya$$b5
000120516 7001_ $$00000-0002-9249-4292$$aBockmayr, Michael$$b6
000120516 7001_ $$aJöhrens, Korinna$$b7
000120516 7001_ $$aEndris, Volker$$b8
000120516 7001_ $$aLier, Amelie$$b9
000120516 7001_ $$aLasitschka, Felix$$b10
000120516 7001_ $$aPenzel, Roland$$b11
000120516 7001_ $$0P:(DE-HGF)0$$aDietel, Manfred$$b12
000120516 7001_ $$0P:(DE-He78)fc949170377b58098e46141d95c72661$$aBrors, Benedikt$$b13$$udkfz
000120516 7001_ $$0P:(DE-He78)5120a331b1c28045c8ca6a8b1c73c95f$$aGröschel, Stefan$$b14$$udkfz
000120516 7001_ $$0P:(DE-He78)157277fe62f07df1732f9d126a51d1b9$$aGlimm, Hanno$$b15$$udkfz
000120516 7001_ $$0P:(DE-HGF)0$$aSchirmacher, Peter$$b16
000120516 7001_ $$aRenner, Marcus$$b17
000120516 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b18$$udkfz
000120516 7001_ $$0P:(DE-HGF)0$$aStenzinger, Albrecht$$b19$$eLast author
000120516 773__ $$0PERI:(DE-600)2645309-5$$a10.1080/2162402X.2017.1279777$$gVol. 6, no. 3, p. e1279777 -$$n3$$pe1279777 -$$tOncoImmunology$$v6$$x2162-402X$$y2017
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