TY  - JOUR
AB  - Background: T cell receptor fusion constructs (TRuC) consist of an antibody-based single chain variable fragment (scFv) fused to a T cell receptor chain (TCR) and allow recognition of cancer cells in an HLA-independent manner. Unlike chimeric antigen receptors (CAR), TRuC are integrated into the TCR complex resulting in a functional chimera with novel specificity, whilst retaining TCR signaling. To further enhance anti-tumor function, we expressed a PD-1-CD28 fusion receptor in TRuC T cells aiming to prevent tumor-induced immune suppression and T cell anergy. Methods: The activation level of engineered T cells was investigated in co-culture experiments with tumor cells followed by quantification of released cytokines using ELISA. To study T cell-mediated tumor cell lysis in vitro, impedance-based real-time tumor cell killing and LDH release was measured. Finally, two xenograft mouse cancer models were employed to explore the therapeutic potential of engineered T cells. Results: In co-culture assays, co-expression of PD-1-CD28 enhanced cytokine production of TRuC T cells. This effect was dependent on PD-L1 to PD-1-CD28 interactions, as blockade of PD-L1 amplified IFN-γ production in unmodified TRuC T cells to a greater level compared to TRuC-PD-1-CD28 T cells. In vivo, PD-1-CD28 co-expression supported the anti-tumor efficacy of TRuC T cells in two xenograft mouse cancer models. Conclusion: Together, these results demonstrate the therapeutic potential of PD-1-CD28 co-expression in TRuC T cells to prevent PD-L1-induced T cell hypofunction.
AU  - Lesch, S.*
AU  - Nottebrock, A.*
AU  - Rataj, F.*
AU  - Heise, C.*
AU  - Endres, S.
AU  - Kobold, S.
C1  - 66758
C2  - 53293
TI  - PD-1-CD28 fusion protein strengthens mesothelin-specific TRuC T cells in preclinical solid tumor models.
JO  - Cell Oncol.
PY  - 2022
SN  - 2211-3428
ER  - 

TY  - JOUR
AB  - PurposeGlioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma.MethodsSOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively.ResultsHigher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells.ConclusionFrom our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.
AU  - Marjanovic Vicentic, J.*
AU  - Drakulic, D.*
AU  - Garcia, I.*
AU  - Vukovic, V.*
AU  - Aldaz, P.*
AU  - Puskas, N.*
AU  - Nikolic, I.*
AU  - Tasic, G.*
AU  - Raicevic, S.*
AU  - Garros-Regulez, L.*
AU  - Sampron, N.*
AU  - Atkinson, M.J.
AU  - Anastasov, N.
AU  - Matheu, A.*
AU  - Stevanovic, M.*
C1  - 54316
C2  - 45487
CY  - Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
SP  - 41-54
TI  - SOX3 can promote the malignant behavior of glioblastoma cells.
JO  - Cell Oncol.
VL  - 42
IS  - 1
PB  - Springer
PY  - 2019
SN  - 2211-3428
ER  - 

TY  - JOUR
AB  - BACKGROUND: The expression of Heat Shock Proteins (HSPs) is increased in various cancers and has been shown to correlate with biological tumor behaviour. This study aimed to investigate the impact of HSP70, HSP60 and HSP27 expression in colon cancer. MATERIAL AND METHODS: HSP expression was determined by immunohistochemistry on a tissue microarray with 355 primary resected colon carcinomas of all stages. Expression patterns were correlated with pathologic features (UICC pTNM category, tumor grading) and survival. RESULTS: Expression of HSP27, HSP60 and HSP70 ranged from negative to high. There was no correlation between HSP27, HSP60 and HSP70 expression among each other and with UICC pT category, presence of lymph node or distant metastases or tumor grading. High HSP70 expression was associated with worse overall survival (p < 0.001) and was an independent prognostic factor (p = 0.004) in multivariate analysis including the pathological parameters mentioned above. For patients without lymph node or distant metastases (UICC stages I/II) and with complete tumor excision, HSP70 expression was the only independent prognostic factor for survival (p = 0.001) and superior to UICC pT category. In left sided UICC stage I/II carcinomas, high HSP27 expression also had adverse prognostic impact and was an independent prognostic factor (p = 0.016) besides HSP70 (p = 0.002). CONCLUSION: High HSP70 and HSP27 expression is associated with worse clinical outcome in colon cancer. Determination of tumoral HSP70 and HSP27 may be used as additional biomarker for risk stratification especially for UICC stage I/II patients.
AU  - Bauer, K.*
AU  - Nitsche, U.*
AU  - Slotta-Huspenina, J.*
AU  - Drecoll, E.*
AU  - von Weyhern, C.H.*
AU  - Rosenberg, R.*
AU  - Höfler, H.
AU  - Langer, R.*
C1  - 8208
C2  - 30079
SP  - 197-205
TI  - High HSP27 and HSP70 expression levels are independent adverse prognostic factors in primary resected colon cancer.
JO  - Cell Oncol.
VL  - 35
IS  - 3
PB  - Springer
PY  - 2012
SN  - 2211-3428
ER  -