Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients
Background Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients w...
Main Authors: | , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMJ Publishing Group
2021-03-01
|
Series: | Journal for ImmunoTherapy of Cancer |
Online Access: | https://jitc.bmj.com/content/9/3/e001458.full |
id |
doaj-a79916ad1b1542e9b504874a3913dd32 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthias Preusser Leonhard Müllauer Anna S Berghoff Sebastian Bauer Gerwin Heller Thomas Brodowicz Wolfgang Lamm Katharina Feldmann Angelika M Starzer Rainer Hamacher Erwin Tomasich Teresa Hatziioannou Stefan Traint Iris M Noebauer-Huhmann Julia Furtner Gabriele Amann Hans-Ulrich Schildhaus |
spellingShingle |
Matthias Preusser Leonhard Müllauer Anna S Berghoff Sebastian Bauer Gerwin Heller Thomas Brodowicz Wolfgang Lamm Katharina Feldmann Angelika M Starzer Rainer Hamacher Erwin Tomasich Teresa Hatziioannou Stefan Traint Iris M Noebauer-Huhmann Julia Furtner Gabriele Amann Hans-Ulrich Schildhaus Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients Journal for ImmunoTherapy of Cancer |
author_facet |
Matthias Preusser Leonhard Müllauer Anna S Berghoff Sebastian Bauer Gerwin Heller Thomas Brodowicz Wolfgang Lamm Katharina Feldmann Angelika M Starzer Rainer Hamacher Erwin Tomasich Teresa Hatziioannou Stefan Traint Iris M Noebauer-Huhmann Julia Furtner Gabriele Amann Hans-Ulrich Schildhaus |
author_sort |
Matthias Preusser |
title |
Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
title_short |
Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
title_full |
Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
title_fullStr |
Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
title_full_unstemmed |
Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
title_sort |
tumor dna methylation profiles correlate with response to anti-pd-1 immune checkpoint inhibitor monotherapy in sarcoma patients |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2021-03-01 |
description |
Background Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.Patients and methods We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.Results 35 patients (median age of 50 (23–81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)–receptor interaction.Conclusions Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma. |
url |
https://jitc.bmj.com/content/9/3/e001458.full |
work_keys_str_mv |
AT matthiaspreusser tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT leonhardmullauer tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT annasberghoff tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT sebastianbauer tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT gerwinheller tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT thomasbrodowicz tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT wolfganglamm tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT katharinafeldmann tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT angelikamstarzer tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT rainerhamacher tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT erwintomasich tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT teresahatziioannou tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT stefantraint tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT irismnoebauerhuhmann tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT juliafurtner tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT gabrieleamann tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients AT hansulrichschildhaus tumordnamethylationprofilescorrelatewithresponsetoantipd1immunecheckpointinhibitormonotherapyinsarcomapatients |
_version_ |
1721419956384432128 |
spelling |
doaj-a79916ad1b1542e9b504874a3913dd322021-05-30T13:00:52ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-03-019310.1136/jitc-2020-001458Tumor DNA methylation profiles correlate with response to anti-PD-1 immune checkpoint inhibitor monotherapy in sarcoma patientsMatthias Preusser0Leonhard Müllauer1Anna S Berghoff2Sebastian Bauer3Gerwin Heller4Thomas Brodowicz5Wolfgang Lamm6Katharina Feldmann7Angelika M Starzer8Rainer Hamacher9Erwin Tomasich10Teresa Hatziioannou11Stefan Traint12Iris M Noebauer-Huhmann13Julia Furtner14Gabriele Amann15Hans-Ulrich Schildhaus16Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Pathology, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Medical Oncology, Sarcoma Center, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Duisburg, GermanyDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Medical Oncology, Sarcoma Center, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Duisburg, GermanyDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDivision of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, AustriaDepartment of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Vienna, AustriaDepartment of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Vienna, AustriaDepartment of Pathology, Medical University of Vienna, Vienna, AustriaInstitute of Pathology, University Hospital Essen, Essen, GermanyBackground Some sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.Patients and methods We retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.Results 35 patients (median age of 50 (23–81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)–receptor interaction.Conclusions Our data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.https://jitc.bmj.com/content/9/3/e001458.full |