TY  - JOUR
A1  - Harter, Patrick N.
A1  - Bernatz, Simon
A1  - Scholz, Alexander
A1  - Zeiner, Pia S.
A1  - Zinke, Jenny
A1  - Kiyose, Makoto
A1  - Blasel, Stella
A1  - Beschorner, Rudi
A1  - Senft, Christian
A1  - Bender, Benjamin
A1  - Ronellenfitsch, Michael W.
A1  - Wikman, Harriet
A1  - Glatzel, Markus
A1  - Meinhardt, Matthias
A1  - Juratli, Tareq A.
A1  - Steinbach, Joachim P.
A1  - Plate, Karl H.
A1  - Wischhusen, Jörg
A1  - Weide, Benjamin
A1  - Mittelbronn, Michel
T1  - Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases
JF  - Oncotarget
N2  - 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.
KW  - B7-H1
KW  - PD-L1
KW  - immunoresistance
KW  - immunosurveillance
KW  - safety
KW  - survival
KW  - expression
KW  - melanoma
KW  - breast cancer
KW  - PC-1 blockade
KW  - cell lung cancer
KW  - tumor-infiltrating lymphocytes
KW  - brain metastases
KW  - PD-1
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137107
VL  - 6
IS  - 38
SP  - 40836
EP  - 40849
ER  -