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PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune
Harriet M Kluger1, Christopher R Zito2, Gabriela Turcu3,4
1Department of Medicine, Yale University School of Medicine, New Haven, Connecticut. harriet.kluger@yale.edu.
Abstract:
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.
Insights
Programmed death-ligand 1 (PD-L1) expression is lower in melanoma than in non-small cell lung cancer (NSCLC) or renal cell carcinoma. Inflammatory cell PD-L1 expression, not tumor cell expression, predicts response to PD-1 inhibitors in melanoma.
Area of Science:
- Oncology
- Immunology
- Biomarker Discovery
Background:
- Programmed death-1 (PD-1) inhibitors are approved for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma.
- Biomarkers predictive of response to PD-1 inhibitors are needed.
- Programmed death-ligand 1 (PD-L1) expression is a widely studied biomarker, showing differential predictive value across tumor types.
Purpose of the Study:
- To investigate differences in PD-L1 expression patterns across melanoma, NSCLC, and renal cell carcinoma.
- To evaluate the predictive value of PD-L1 expression in melanoma patients treated with PD-1 inhibitors.
Main Methods:
- Tissue microarrays of NSCLC, renal cell carcinoma, and melanoma tumors were analyzed.
- A panel of cell lines was used to confirm expression patterns.
- PD-L1 expression was quantified using immunofluorescence in 65 melanoma patients treated with PD-1 or CTLA-4 inhibitors.
Main Results:
- PD-L1 expression was significantly higher in NSCLC, followed by renal cell carcinoma, and lowest in melanoma.
- In melanoma, PD-L1 was expressed on either tumor cells or immune-infiltrating cells.
- PD-L1 expression on immune-infiltrating cells, but not tumor cells, was strongly associated with progression-free and overall survival in melanoma patients treated with PD-1 inhibitors.
Conclusions:
- Melanoma exhibits lower PD-L1 expression on tumor cells compared to NSCLC and renal cell carcinoma.
- The efficacy of PD-1 inhibitors in melanoma may be attributed to PD-L1 expression on tumor-associated inflammatory cells.
- Further research is required to validate the predictive role and biological significance of inflammatory cell PD-L1 expression in melanoma.
