Research Papers:

Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases

Patrick N. Harter _, Simon Bernatz, Alexander Scholz, Pia S. Zeiner, Jenny Zinke, Makoto Kiyose, Stella Blasel, Rudi Beschorner, Christian Senft, Benjamin Bender, Michael W. Ronellenfitsch, Harriet Wikman, Markus Glatzel, Matthias Meinhardt, Tareq A. Juratli, Joachim P. Steinbach, Karl H. Plate, Jörg Wischhusen, Benjamin Weide and Michel Mittelbronn

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Oncotarget. 2015; 6:40836-40849. https://doi.org/10.18632/oncotarget.5696

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Patrick N. Harter1,2,3, Simon Bernatz1, Alexander Scholz1,4, Pia S. Zeiner1,5, Jenny Zinke1, Makoto Kiyose6, Stella Blasel6, Rudi Beschorner7, Christian Senft2,3,8, Benjamin Bender9, Michael W. Ronellenfitsch2,3,10, Harriet Wikman11, Markus Glatzel12, Matthias Meinhardt13, Tareq A. Juratli14, Joachim P. Steinbach2,3,10, Karl H. Plate1,2,3, Jörg Wischhusen15, Benjamin Weide16,17, Michel Mittelbronn1,2,3

1Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

4Laboratory of Immunology and Vascular Biology, Stanford School of Medicine, Palo Alto, CA, USA

5Department of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany

6Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany

7Department of Neuropathology, University of Tuebingen, Tuebingen, Germany

8Department of Neurosurgery, University of Frankfurt am Main, Frankfurt am Main, Germany

9Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany

10Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany

11Department of Tumor biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

12Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

13Department of Pathology, University of Dresden, Dresden, Germany

14Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Dresden, Germany

15Department of Gynecology, University of Wuerzburg, Wuerzburg, Germany

16Department of Dermatology, University of Tuebingen, Tuebingen, Germany

17Department of Immunology, University of Tuebingen, Tuebingen, Germany

Correspondence to:

Michel Mittelbronn, e-mail: [email protected]

Patrick N. Harter, e-mail: [email protected]

Keywords: tumor-infiltrating lymphocytes, brain metastases, PD-1, PD-L1

Received: April 21, 2015     Accepted: September 16, 2015     Published: October 16, 2015


The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors.

Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed.

TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537).

In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.

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