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

Standard

PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma. / Budczies, Jan; Mechtersheimer, Gunhild; Denkert, Carsten; Klauschen, Frederick; Mughal, Sadaf S; Chudasama, Priya; Bockmayr, Michael; Jöhrens, Korinna; Endris, Volker; Lier, Amelie; Lasitschka, Felix; Penzel, Roland; Dietel, Manfred; Brors, Benedikt; Gröschel, Stefan; Glimm, Hanno; Schirmacher, Peter; Renner, Marcus; Fröhling, Stefan; Stenzinger, Albrecht.

In: ONCOIMMUNOLOGY, Vol. 6, No. 3, 2017, p. e1279777.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Budczies, J, Mechtersheimer, G, Denkert, C, Klauschen, F, Mughal, SS, Chudasama, P, Bockmayr, M, Jöhrens, K, Endris, V, Lier, A, Lasitschka, F, Penzel, R, Dietel, M, Brors, B, Gröschel, S, Glimm, H, Schirmacher, P, Renner, M, Fröhling, S & Stenzinger, A 2017, 'PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma', ONCOIMMUNOLOGY, vol. 6, no. 3, pp. e1279777. https://doi.org/10.1080/2162402X.2017.1279777

APA

Budczies, J., Mechtersheimer, G., Denkert, C., Klauschen, F., Mughal, S. S., Chudasama, P., Bockmayr, M., Jöhrens, K., Endris, V., Lier, A., Lasitschka, F., Penzel, R., Dietel, M., Brors, B., Gröschel, S., Glimm, H., Schirmacher, P., Renner, M., Fröhling, S., & Stenzinger, A. (2017). PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma. ONCOIMMUNOLOGY, 6(3), e1279777. https://doi.org/10.1080/2162402X.2017.1279777

Vancouver

Budczies J, Mechtersheimer G, Denkert C, Klauschen F, Mughal SS, Chudasama P et al. PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma. ONCOIMMUNOLOGY. 2017;6(3):e1279777. https://doi.org/10.1080/2162402X.2017.1279777

Bibtex

@article{613b0d10786f43749406da58576a5bcc,
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 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.",
keywords = "Journal Article",
author = "Jan Budczies and Gunhild Mechtersheimer and Carsten Denkert and Frederick Klauschen and Mughal, {Sadaf S} and Priya Chudasama and Michael Bockmayr and Korinna J{\"o}hrens and Volker Endris and Amelie Lier and Felix Lasitschka and Roland Penzel and Manfred Dietel and Benedikt Brors and Stefan Gr{\"o}schel and Hanno Glimm and Peter Schirmacher and Marcus Renner and Stefan Fr{\"o}hling and Albrecht Stenzinger",
year = "2017",
doi = "10.1080/2162402X.2017.1279777",
language = "English",
volume = "6",
pages = "e1279777",
journal = "ONCOIMMUNOLOGY",
issn = "2162-402X",
publisher = "Taylor & Francis",
number = "3",

}

RIS

TY - JOUR

T1 - PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma

AU - Budczies, Jan

AU - Mechtersheimer, Gunhild

AU - Denkert, Carsten

AU - Klauschen, Frederick

AU - Mughal, Sadaf S

AU - Chudasama, Priya

AU - Bockmayr, Michael

AU - Jöhrens, Korinna

AU - Endris, Volker

AU - Lier, Amelie

AU - Lasitschka, Felix

AU - Penzel, Roland

AU - Dietel, Manfred

AU - Brors, Benedikt

AU - Gröschel, Stefan

AU - Glimm, Hanno

AU - Schirmacher, Peter

AU - Renner, Marcus

AU - Fröhling, Stefan

AU - Stenzinger, Albrecht

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1080/2162402X.2017.1279777

DO - 10.1080/2162402X.2017.1279777

M3 - SCORING: Journal article

C2 - 28405504

VL - 6

SP - e1279777

JO - ONCOIMMUNOLOGY

JF - ONCOIMMUNOLOGY

SN - 2162-402X

IS - 3

ER -