ABSTRACT
Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet.
In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD-L1 levels might be caused by an inflammatory tumor type – independent of tumoral PD-L1 expression.
Disclosure of potential conflicts of interest
Stefan Boeck has received honoraria for scientific presentations from Celgene and Roche, research funding from Celgene, Clovis Oncology and Roche, travel grants from Celgene and Roche and acted as consultant for Celgene and Baxalta.
Michael Haas has received honoraria for scientific presentations from Celgene, research funding (for his institution) from Boehringer Ingelheim and Roche, travel grants from Boehringer Ingelheim and Celgene.
Dominik Modest has received Honoraria and research funding from Roche.
Volker Heinemann has received honoraria for scientific presentations from Baxalta, Celgene and Roche, research funding from Celgene and Roche and acted as consultant for Baxalta, Celgene and Roche.
All other authors declare no conflict of interest.
Acknowledgements
This work is part of the doctoral thesis of Marie-Louise Legenstein and Verena Rösgen.
Funding
Stephan Kruger is supported by a grant from the Friedrich-Baur-Stiftung, Munich.
Author contributions
Stephan Kruger and Stefan Boeck: analysis and interpretation of data; drafting of the manuscript. Stephan Kruger, Stefan Holdenrieder and Stefan Boeck: study concept and design. Marie-Louise Legenstein and Verena Roesgen: acquisition of data, collection of serum and tumor samples. Steffen Ormanns and Thomas Kirchner: pathological review of tumor samples and analysis of tumoral PD-L1 expression and tumoral CD3C T cell infiltration. Stephan Kruger, Michael Haas, Dominik Paul Modest, Christoph Benedikt Westphalen, Volker Heinemann and Stefan Boeck: provision of patient data. Stephan Kruger, Marie-Louise Legenstein, Verena R€osgen, Michael Haas, Dominik Paul Modest, Christoph Benedikt Westphalen, Steffen Ormanns, Thomas Kirchner, Volker Heinemann, Stefan Holdenrieder and Stefan Boeck: critical revision of the final manuscript.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethics committee (Approval number 284–10, ethics committee Ludwig-Maximilians-University Munich).