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The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer

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Abstract

Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1+ TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1+ TIL were present in 104 (15.8 %) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1+ TIL was associated with a significantly worse overall survival (HR = 2.736, p < 0.001). In subset analyses, the presence of PD-1+ TIL was associated with significantly worse overall survival in the luminal B HER2− subtype (HR = 2.678, p < 0.001), the luminal B HER2+ subtype (HR = 3.689, p < 0.001), and the basal-like subtype (HR = 3.140, p < 0.001). This is the first study to demonstrate that the presence of PD-1+ TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.

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Acknowledgments

This study was supported by a research grant of the Swiss National Foundation (SNF) (PBBSP3-138709). We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Mo., for the use of the Biostatistics Core. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA091842. We thank Professor D. Craig Allred for his contribution to the development of the BTLA immunihistochemical assay. We thank Professor Alexandar Tzankov for his valuable insights and critical review of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, Basel, 4031, Switzerland

    S. Muenst & E. C. Obermann

  2. Department of Surgery, Washington University School of Medicine, St. Louis, USA

    S. Muenst, S. D. Soysal & W. E Gillanders

  3. Department of Surgery, University Hospital Basel, Basel, Switzerland

    S. D. Soysal & D. Oertli

  4. Division of Biostatistics, Washington University School of Medicine, St. Louis, USA

    F. Gao

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  1. S. Muenst
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Correspondence to S. Muenst.

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S. Muenst and S. D. Soysal have contributed equally to this study.

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Muenst, S., Soysal, S.D., Gao, F. et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 139, 667–676 (2013). https://doi.org/10.1007/s10549-013-2581-3

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