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

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.

Oncotarget. 2015 Oct 16 [Epub ahead of print]

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, Michel Mittelbronn

Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Department of Neuropathology, University of Tuebingen, Tuebingen, Germany. , German Cancer Consortium (DKTK), Heidelberg, Germany. , Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany. , German Cancer Consortium (DKTK), Heidelberg, Germany. , Department of Tumor biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. , Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. , Department of Pathology, University of Dresden, Dresden, Germany. , Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Dresden, Germany. , German Cancer Consortium (DKTK), Heidelberg, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany. , Department of Gynecology, University of Wuerzburg, Wuerzburg, Germany. , Department of Dermatology, University of Tuebingen, Tuebingen, Germany. , Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.

PubMed

E-Newsletters

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.

Subscribe