TY  - JOUR
A1  - Jungwirth, Gerhard
A1  - Yu, Tao
A1  - Moustafa, Mahmoud
A1  - Rapp, Carmen
A1  - Warta, Rolf
A1  - Jungk, Christine
A1  - Sahm, Felix
A1  - Dettling, Steffen
A1  - Zweckberger, Klaus
A1  - Lamszus, Katrin
A1  - Senft, Christian
A1  - Loehr, Mario
A1  - Keßler, Almuth F.
A1  - Ketter, Ralf
A1  - Westphal, Manfred
A1  - Debus, Juergen
A1  - von Deimling, Andreas
A1  - Simon, Matthias
A1  - Unterberg, Andreas
A1  - Abdollahi, Amir
A1  - Herold-Mende, Christel
T1  - Identification of KIF11 as a Novel Target in Meningioma
JF  - Cancers
N2  - Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
KW  - meningioma
KW  - KIF
KW  - kinesin
KW  - KIF11
KW  - NCH93
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197402
SN  - 2072-6694
VL  - 11
IS  - 4
ER  - 
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  -