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