PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors

• Published in: Clinical cancer research Vol. 23; no. 15; pp. 4270 - 4279
• Main Authors: Kluger, Harriet M., Zito, Christopher R., Turcu, Gabriela, Baine, Marina K., Zhang, Hongyi, Adeniran, Adebowale, Sznol, Mario, Rimm, David L., Kluger, Yuval, Chen, Lieping, Cohen, Justine V., Jilaveanu, Lucia B.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2017
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies; Antibodies, Monoclonal - administration & dosage; Antineoplastic Agents - administration & dosage; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Biotechnology; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; CTLA-4 protein; Experimental design; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune checkpoint; Immunofluorescence; Inflammation; Inhibitors; Lung cancer; Male; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Middle Aged; Monoclonal antibodies; Non-small cell lung carcinoma; Patients; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Renal cell carcinoma; Studies; Targeted cancer therapy; Tissue Array Analysis; Tumor cells; Tumors
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3146

Purpose: With recent approval of inhibitors of PD-1 in melanoma, non–small cell lung cancer (NSCLC) and renal cell carcinoma, extensive efforts are under way to develop biomarkers predictive of response. PD-L1 expression has been most widely studied, and is more predictive in NSCLC than renal cell carcinoma or melanoma. We therefore studied differences in expression patterns across tumor types. Experimental Design: We used tissue microarrays with tumors from NSCLC, renal cell carcinoma, or melanoma and a panel of cell lines to study differences between tumor types. Predictive studies were conducted on samples from 65 melanoma patients treated with PD-1 inhibitors alone or with CTLA-4 inhibitors, characterized for outcome. PD-L1 expression was studied by quantitative immunofluorescence using two well-validated antibodies. Results: PD-L1 expression was higher in NSCLC specimens than renal cell carcinoma, and lowest in melanoma (P = 0.001), and this finding was confirmed in a panel of cell lines. In melanoma tumors, PD-L1 was expressed either on tumor cells or immune-infiltrating cells. The association between PD-L1 expression in immune-infiltrating cells and progression-free or overall-survival in melanoma patients treated with ipilimumab and nivolumab was stronger than PD-L1 expression in tumor cells, and remained significant on multivariable analysis. Conclusions: PD-L1 expression in melanoma tumor cells is lower than NSCLC or renal cell carcinoma cells. The higher response rate in melanoma patients treated with PD-1 inhibitors is likely related to PD-L1 in tumor-associated inflammatory cells. Further studies are warranted to validate the predictive role of inflammatory cell PD-L1 expression in melanoma and determine its biological significance. Clin Cancer Res; 23(15); 4270–9. ©2017 AACR.