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Journal of Neuro-Oncology

, Volume 130, Issue 1, pp 19–29 | Cite as

Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC)

  • Anna Sophie Berghoff
  • Gerda Ricken
  • Dorothee Wilhelm
  • Orsolya Rajky
  • Georg Widhalm
  • Karin Dieckmann
  • Peter Birner
  • Rupert Bartsch
  • Matthias Preusser
Laboratory Investigation

Abstract

Brain metastases (BM) are frequent in small cell lung cancer (SCLC). Novel insights into their pathobiology are needed for development of better therapies. We investigated tumor-infiltrating lymphocyte (TIL) subsets (CD3+, CD8+, CD45RO+, FOXP3+ and PD-1+) and expression of PD-L1 in a series of 32 SCLC BM specimens and four matched primary tumor specimens using immunohistochemistry. 30/32 (93.8 %) BM specimens showed TIL infiltration. CD3+ TILs were observed in 30/32 (93.8 %) BM specimens, CD8+ TILs in 25/32 (78.1 %), CD45RO+ TILs in 15/32 (46.9 %), FOXP3+ TILs in 15/32 (46.9 %) and PD-1+ TILs in 1/32 (3.1 %) BM specimens. Patients with infiltration of CD45RO+ TILS had a significantly longer median survival time (11 months; 95 % CI 0.000–26.148) as compared to patients without the presence of CD45RO+ TILs (5 months; 95 % CI 0.966–9.034; p = 0.007; log rank test). Membranous PD-L1 on tumor cells was observed in 24/32 (75.0 %) BM specimens, with 11/32 (34.4 %) cases showing PD-L1 expression in over 5 % of viable BM tumor cells. PD-L1 expression on TILs was seen in 8/32 (25.0 %) and on tumor infiltrating macrophages in 9/32 (28.1 %) cases. Patients with PD-L1 expression on TILs presented with improved survival prognosis (6 versus 29 months; p = 0.002; log rank test). Among matched primary tumors, all (4/4; 100 %) specimens showed TIL infiltration, while PD-L1 expression found in only 1/4 (25.0 %) specimen. TIL infiltration and PD-L1 expression are commonly found in SCLC BM and presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seem to associate with favorable survival times. Our data suggest an active immune microenvironment in SCLC BM that may be targetable by immune-modulating drugs.

Keywords

Small cell lung cancer Brain metastases Tumor infiltrating lymphocytes PD-L1 expression Immune checkpoint inhibitor 

Notes

Acknowledgments

We thank Dr. Lieping Chen (Yale) for providing anti-PD-L1 antibody (5H1) for this study. We thank Franziska Vogler, Philip Kresl and Tobias Raymann for excellence technical assistance.

Funding

The costs for this project were covered by the research budget of the Medical University of Vienna and the grant “Initiative Krebsforschung” with the project title “Tumorimmunologie von Hirnmetastasen”.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11060_2016_2216_MOESM1_ESM.tif (10.4 mb)
Supplemental Fig. 1: Control tissue staining results A Immunohistochemistry for PD1 in a lymph node (magnification ×200) B Immunohistochemistry for PD1 in placenta (magnification ×200 ). (TIF 10614 KB)
11060_2016_2216_MOESM2_ESM.tif (5.8 mb)
Supplemental Fig. 2: A PD-L1 expression in macrophages (errors indicate macrophages; magnification ×200 ) B PD-L1 expression in tumor infiltrating lymphocytes (errors indicate TILs; magnification ×200 ) C CD3+ TILs in the same specimen shown in B (magnification ×200 ). (TIF 5907 KB)
11060_2016_2216_MOESM3_ESM.doc (54 kb)
Supplementary material 3 (DOC 53 KB)

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anna Sophie Berghoff
    • 1
    • 2
  • Gerda Ricken
    • 2
    • 3
  • Dorothee Wilhelm
    • 4
  • Orsolya Rajky
    • 1
    • 2
  • Georg Widhalm
    • 3
    • 5
  • Karin Dieckmann
    • 2
    • 6
  • Peter Birner
    • 2
    • 7
  • Rupert Bartsch
    • 1
    • 2
  • Matthias Preusser
    • 1
    • 2
  1. 1.Department of Medicine I and Comprehensive Cancer Center CNS Unit (CCC-CNS)Medical University of ViennaViennaAustria
  2. 2.Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  3. 3.Institute of NeurologyMedical University of ViennaViennaAustria
  4. 4.Department for Radiology and Nuclear MedicineMedical University of ViennaViennaAustria
  5. 5.Department of NeurosurgeryMedical University of ViennaViennaAustria
  6. 6.Department of RadiotherapyMedical University of ViennaViennaAustria
  7. 7.Institute of Clinical PathologyMedical University of ViennaViennaAustria

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