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2.
Nature ; 561(7723): 331-337, 2018 09.
Article in English | MEDLINE | ID: mdl-30185905

ABSTRACT

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.

3.
Cancer Res ; 78(2): 489-500, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29183891

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8+ TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.Significance: These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature. Cancer Res; 78(2); 489-500. ©2017 AACR.


Subject(s)
Cell- and Tissue-Based Therapy , Immunotherapy , Lung Neoplasms/therapy , Neoplasm Proteins/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, Cell Surface/metabolism , T-Lymphocytes/transplantation , Triple Negative Breast Neoplasms/therapy , Animals , Apoptosis , Biomarkers, Tumor , Case-Control Studies , Cell Proliferation , Female , Follow-Up Studies , Humans , Lung Neoplasms/immunology , Lung Neoplasms/secondary , Mice , Microfilament Proteins , Prognosis , Survival Rate , T-Lymphocytes/immunology , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
4.
Sci Rep ; 7(1): 8022, 2017 08 14.
Article in English | MEDLINE | ID: mdl-28808307

ABSTRACT

Aggresomes are transient microtubule-dependent inclusion bodies that sequester misfolded proteins and are ultimately removed by autophagy. Here we report the generation of a choroid plexus carcinoma cell line; Children's Cancer Hospital Egypt (CCHE)-45, which is characterized by the constitutive formation of aggresomes. When examining the autophagy pathway as the main route for aggresomes clearance, CCHE-45 cells displayed increased autophagy flux mediated by MAP1LC3B. MAP1LC3A-Variant1 gene expression was silenced by promoter methylation. Restoring MAP1LC3A-Variant1 expression resulted in the formation of MAP1LC3A positive autophagosmes and the disruption of the aggresomes' vimentin cage independent of MAP1LC3B positive autophagosomes. Our data supports the notion that basal quality control autophagy and vimentin cage clearance in CCHE-45 are mediated by MAP1LC3A. Hence we propose that absence of MAP1LC3A disrupts the autophagic pathway and leads to the failure of aggresome vimentin cage degradation. Consequently, this could represent a targetable pathway in autophagy-dependent cancers.


Subject(s)
Autophagy , Carcinoma/genetics , Choroid Plexus Neoplasms/genetics , Microtubule-Associated Proteins/genetics , Vimentin/metabolism , Adolescent , Autophagosomes/metabolism , Carcinoma/metabolism , Carcinoma/pathology , Cell Line, Tumor , Cells, Cultured , Child , Choroid Plexus Neoplasms/metabolism , Choroid Plexus Neoplasms/pathology , Female , Gene Silencing , HEK293 Cells , Humans , Male , Microtubule-Associated Proteins/metabolism
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