Bibhusal Thapa1, Adriana Salcedo2, Xihui Lin2, Marzena Walkiewicz3, Carmel Murone4, Malaka Ameratunga5, Khashyar Asadi6, Siddhartha Deb3, Stephen Arthur Barnett7, Simon Knight7, Paul Mitchell5, D Neil Watkins8, Paul C Boutros9, Thomas John10. 1. Department of Medicine, University of Melbourne, Parkville, Victoria, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. 2. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada. 3. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. 4. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; Department of Pathology, Austin Health, Heidelberg, Victoria, Australia. 5. Department of Medical Oncology, Austin Health, Olivia-Newton John Cancer and Wellness Centre, Heidelberg, Victoria, Australia. 6. Department of Pathology, Austin Health, Heidelberg, Victoria, Australia. 7. Department of Thoracic Surgery, Austin Health, Heidelberg, Victoria, Australia. 8. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. 9. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. 10. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; Department of Medical Oncology, Austin Health, Olivia-Newton John Cancer and Wellness Centre, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia. Electronic address: tom.john@onjcri.org.au.
Abstract
INTRODUCTION: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features. METHODS: Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables. RESULTS: Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression. CONCLUSIONS: PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.
INTRODUCTION: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features. METHODS: Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables. RESULTS: Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression. CONCLUSIONS:PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.
Authors: Raffit Hassan; Anish Thomas; John J Nemunaitis; Manish R Patel; Jaafar Bennouna; Franklin L Chen; Jean-Pierre Delord; Afshin Dowlati; Samith T Kochuparambil; Matthew H Taylor; John D Powderly; Ulka N Vaishampayan; Claire Verschraegen; Hans Juergen Grote; Anja von Heydebreck; Kevin Chin; James L Gulley Journal: JAMA Oncol Date: 2019-03-01 Impact factor: 31.777