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

2015; Impact Journals LLC; Volume: 6; Issue: 38 Linguagem: Inglês

10.18632/oncotarget.5696

1949-2553

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

Lung Cancer Research Studies

// Patrick N. Harter 1, 2, 3 , Simon Bernatz 1 , Alexander Scholz 1, 4 , Pia S. Zeiner 1, 5 , Jenny Zinke 1 , Makoto Kiyose 6 , Stella Blasel 6 , Rudi Beschorner 7 , Christian Senft 2, 3, 8 , Benjamin Bender 9 , Michael W. Ronellenfitsch 2, 3, 10 , Harriet Wikman 11 , Markus Glatzel 12 , Matthias Meinhardt 13 , Tareq A. Juratli 14 , Joachim P. Steinbach 2, 3, 10 , Karl H. Plate 1, 2, 3 , Jörg Wischhusen 15 , Benjamin Weide 16, 17 , Michel Mittelbronn 1, 2, 3 1 Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany 2 German Cancer Consortium (DKTK), Heidelberg, Germany 3 German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Laboratory of Immunology and Vascular Biology, Stanford School of Medicine, Palo Alto, CA, USA 5 Department of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany 6 Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany 7 Department of Neuropathology, University of Tuebingen, Tuebingen, Germany 8 Department of Neurosurgery, University of Frankfurt am Main, Frankfurt am Main, Germany 9 Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany 10 Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany 11 Department of Tumor biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 12 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 13 Department of Pathology, University of Dresden, Dresden, Germany 14 Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Dresden, Germany 15 Department of Gynecology, University of Wuerzburg, Wuerzburg, Germany 16 Department of Dermatology, University of Tuebingen, Tuebingen, Germany 17 Department of Immunology, University of Tuebingen, Tuebingen, Germany Correspondence to: Michel Mittelbronn, e-mail: michel.mittelbronn@kgu.de Patrick N. Harter, e-mail: patrick.harter@kgu.de Keywords: tumor-infiltrating lymphocytes, brain metastases, PD-1, PD-L1 Received: April 21, 2015 Accepted: September 16, 2015 Published: October 16, 2015 ABSTRACT 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.