KDM6B Inhibition Has Anti-Tumor Activity in Anaplastic Wilms Tumor Cells Associated with WT1 And MYCN Pathway Silencing

BACKGROUND: Block of programmed cell death protein 1 (PD-1) interaction with its ligand, PD-L1, enhances anti-tumor activity. OBJECTIVES: We aimed to assess the association between PD-L1 expression in tumor cells and CD8+ tumor infiltrating T cells (TILs) as well as soluble (s)PD-L1 serum levels in patients with triple negative breast cancer (TNBC) compared to triple positive (TPBC). METHODS: A total of 113 tumor sections and 133 serum samples were available from 144 patients with breast cancer (72 TNBC and 72 TPBC). Dual immunohistochemistry staining was applied to determine differential PD-L1 expression in tumor cells and CD8+ TILs. Soluble PD-L1 serum levels were also evaluated in patients compared to 40 healthy women by ELISA method. RESULTS: Despite TPBC patients which were mostly grades 1/2, TNBC patients were grade 3 (72% versus 66.7%, P < 0.001). Most of the TNBC patients were stages I/II, whereas most of the TPBC patients were stages III/IV (57.3% versus 68.3%,P = 0.005). There was no difference in tumor size and metastasis between TNBC and TPBC patients, although the number of involved lymph nodes was significantly more in TPBC patients (P = 0.0012). PD-L1 expression was detected in 11.5% of samples mostly in TNBC subtype and was associated with advanced grades (P = 0.039). There was no relationship between PD-L1 expression and tumor stage. PD-L1 expression in CD8+ TILs was nonsignificantly higher than tumor cells. Serum levels of sPD-L1 showed no difference between patients and healthy women. We found no correlation between PD-L1 expression in tumor lesions and serum levels of sPD-L1 in patients. CONCLUSION: PD-L1 expression was more detected in our patients with TNBC. It seems that, these patients who are resistant to standard chemotherapy regimens may get benefit from PD-L1 inhibition therapy and because of its low serum levels, sPD-L1 cannot interfere with this therapy.

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Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells.

Molecular and Cellular Biology ◽

10.1128/mcb.9.4.1799 ◽

1989 ◽

Vol 9 (4) ◽

pp. 1799-1803 ◽

Cited By ~ 145

Author(s):

A E Reeve ◽

S A Sih ◽

A M Raizis ◽

A P Feinberg

Keyword(s):

Mental Retardation ◽

Tumor Cells ◽

Germ Line ◽

Wilms Tumor ◽

Globin Gene ◽

Allelic Loss ◽

Chromosomal Band ◽

Chromosome 11 ◽

Gamma Globin ◽

Wagr Syndrome

Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.

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163 Improved anti-tumor activity of next-generation TCR-engineered T cells through CD8 co-expression

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.163 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A173-A173

Author(s):

Gagan Bajwa ◽

Justin Gunesch ◽

Inbar Azoulay-Alfaguter ◽

Melinda Mata ◽

Ali Mohamed ◽

...

Keyword(s):

T Cells ◽

Tumor Cells ◽

Solid Tumor ◽

Cd4 T Cells ◽

Tumor Response ◽

Hla Class I ◽

Next Generation ◽

Engineered T Cells ◽

Anti Tumor Activity

BackgroundSuccessful targeting of solid tumors with TCR-engineered T cells (TCR-T) will require eliciting of antigen-specific, multi-dimensional, sustained anti-tumor immune response by infused T cells while overcoming the suppressive tumor microenvironment. First-generation TCR-T approaches have demonstrated clinical efficacy in some solid cancers. However, effective treatment across several solid tumor indications may require engineered T cells with enhanced anti-tumor activity. Here, we show pre-clinical data from one of the engineering approaches currently being developed for next-generation ACTengine® TCR-T product candidates. We evaluated the impact of co-expression of different CD8 co-receptors on functionality of CD4+ and CD8+ T cells genetically modified with an HLA class I-restricted TCR and determined the depth and durability of anti-tumor response in vitro.MethodsHere, we used a PRAME-specific TCR currently being tested in the ACTengine® IMA203 clinical trial. T cells expressing either the TCR alone or co-expressing the TCR and CD8α homodimer (TCR.CD8α) or CD8αβ heterodimer (TCR.CD8αβ) were characterized for transgene expression, antigen-recognition, and functional efficacy in vitro. Comprehensive evaluation of CD4+ T cells expressing TCR.CD8α or TCR.CD8αβ was performed focusing on cytotoxic potential and the breadth of cytokine response against target-positive tumor cell lines.ResultsIntroduction of CD8α or CD8αβ enabled detection of transgenic TCR on the surface of CD4+ T cells via HLA multimer-guided flow cytometry otherwise lacking in the TCR only transduced T cells. Co-expression of either form of CD8 co-receptor endowed CD4+ T cells with the ability to recognize and kill target positive tumor cells; however, genetic modification with TCR.CD8αβ led to more pronounced CD4+ T cell activation as compared to TCR.CD8α. Most distinct differences were observed in the breadth and magnitude of cytokine responses, less in cytotoxic activity against tumor cells. T cells expressing TCR.CD8αβ showed superior induction of Th1 cytokines e.g. IFNγ, TNFα, IL-2, GM-CSF in vitro upon antigen stimulation as compared to TCR.CD8α-T cells. Additionally, TCR.CD8αβ T cells demonstrated more efficient engagement with antigen-presenting cells and consequently, modulation of cytokine response than TCR.CD8α-T cells.ConclusionsOur findings illustrate that engaging CD4+ T cells via CD8 co-expression potentiates anti-tumor activity of HLA class I restricted TCR-T cells in vitro. The pleiotropic effects mediated by activated CD4+ T cells including acquired cytotoxicity may potentially improve outcomes in solid tumor patients when applied clinically. In addition, the differential functional profile of TCR-T cells co-expressing either CD8α or CD8αβ suggests that optimizing the type of co-receptor is relevant to maximize anti-tumor response.

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MicroRNA-27a-5p inhibits proliferation, migration and invasion and promotes apoptosis of Wilms tumor cell by targeting PBOV1

10.1101/2021.08.25.457737 ◽

2021 ◽

Author(s):

zhengtuan guo ◽

qiang yv ◽

chunlin miao ◽

wenan ge ◽

peng li

Keyword(s):

Tumor Cells ◽

Wilms Tumor ◽

Suppressive Effect ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tumor Tissues ◽

And Function ◽

Tumor Suppressive Effect

Wilms tumor is the most common type of renal tumor in children. MicroRNAs (miRNA) are small non-coding RNAs that play crucial regulatory roles in tumorigenesis. We aimed to study the expression profile and function of miR-27a-5p in Wilms tumor. MiR-27a-5p expression was downregulated in human Wilms tumor tissues. Functionally, overexpression of miR-27a-5p promoted cell apoptosis of Wilms tumor cells. Furthermore, upregulated miR-27a-5p delayed xenograft Wilms tumor tumorigenesis in vivo. Bioinformatics analysis predicted miR-27-5p directly targeted to the 3’-untranslated region (UTR) of PBOV1 and luciferase reporter assay confirmed the interaction between miR-27a-5p and PBOV1. The function of PBOV1 in Wilms tumor was evaluated in vitro and knockdown of PBOV1 dampened cell migration. In addition, overexpression of PBOV1 antagonized the tumor-suppressive effect of miR-27a-5p in Wilms tumor cells. Collectively, our findings reveal the regulatory axis of miR-27-5p/PBOV1 in Wilms tumor and miR-27a-5p might serve as a novel therapeutic target in Wilms tumor.

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In vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET

Oncotarget ◽

10.18632/oncotarget.17900 ◽

2017 ◽

Vol 8 (43) ◽

pp. 73766-73773 ◽

Cited By ~ 6

Author(s):

Sachiko Arai ◽

Kenji Kita ◽

Azusa Tanimoto ◽

Shinji Takeuchi ◽

Koji Fukuda ◽

...

Keyword(s):

Tumor Cells ◽

Anti Tumor Activity

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Anti-tumor activity of interleukin-2-producing tumor cells and recombinant interleukin 12 against mouse glioma cells located in the central nervous system

International Journal of Cancer ◽

10.1002/(sici)1097-0215(19990129)80:3<425::aid-ijc15>3.0.co;2-7 ◽

1999 ◽

Vol 80 (3) ◽

pp. 425-430 ◽

Cited By ~ 28

Author(s):

Tetsuro Kikuchi ◽

Tatsuhiro Joki ◽

Saburo Saitoh ◽

Yuichi Hata ◽

Toshiaki Abe ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Tumor Cells ◽

Interleukin 2 ◽

Glioma Cells ◽

Interleukin 12 ◽

The Central Nervous System ◽

Anti Tumor Activity ◽

Mouse Glioma

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Wilms tumor-suppressing peptide inhibits proliferation and induces apoptosis of Wilms tumor cells in vitro and in vivo

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-019-03003-0 ◽

2019 ◽

Vol 145 (10) ◽

pp. 2457-2468 ◽

Cited By ~ 1

Author(s):

Wei Zhao ◽

Juan Li ◽

Ping Li ◽

Fei Guo ◽

Pengfei Gao ◽

...

Keyword(s):

Tumor Cells ◽

Wilms Tumor

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Platelet Interaction with Tumor Cells

10.1055/s-0039-1689591 ◽

1975 ◽

Author(s):

G. Gasic ◽

T. Gasic ◽

B. Hsu ◽

P. Koch ◽

S. Niewiarowski

Keyword(s):

Tumor Cells ◽

Gamma Globulin ◽

Wilms Tumor ◽

Preliminary Evidence ◽

Human Tumors ◽

Research Support ◽

Mouse Tumors ◽

Adp Release ◽

Colonic Adenocarcinomas ◽

Mammary Adenocarcinomas

Previous investigations demonstrated that mouse tumors cause platelet aggregation (PA) and increase platelet turnover. Depletion of platelets by neuraminidase and inhibition of PA by aspirin reduced the munber of metastases (Gasic et al., Int. J. Cancer 11, 704, 1973). The purpose of this investigation was to study further interaction of cells from various mouse and human tumors with platelets. Cells of 7 mouse tumors (1 mammary adenocarcinomas, 5 sarcomas, I melanoma) and 14 human tumors (8 breast, 3 colonic adenocarcinomas, 1 cancer of the ureter, 1 Wilms tumor, and 1 neuroblastoma) aggregated homologous platelets suspended in heparinized plasma. Three mouse tumors (2 mammary and 1 sarcoma) and 5 human tumors (2 breast, 1 sarcoma, 1 Wilms, and 1 neuroblastoma) did not. PA was accompanied by the release of radio-activity from 14C-serotonin labeled platelets (range 15–90%). PA activity was not correlated with fibrinolytic or procoagulant activity. The contribution of plasminogen activators, thrombin, and tumor immune complexes has been excluded. However, gamma globulin of tumor bearing mice contained a “blocking factor” which delayed PA. Since enzymatic removal of ADP reduced PA it is possible that the ADP release either by tumors or by platelets played a contributory role. The pattern of PA by tumor cells rossembled that induced by collagen. Indeed preliminary evidence suggests that collagen-like material associated with tumor cells might be involved in platelet adherence to these cells and subsequent aggregation.(Supported by NIH Grants CA-15728, HL 14217. HL 15226, and by a Univ. of Penna.’s General Research Support Grant.)

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