A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

Abstract Among the strategies allowing cancer cells to escape the immune system, the presence of TGF-b in the tumor micro-environment is one of the most potent. However, TGF-b is secreted in an inactive form and mechanisms responsible for its activation within the tumor remain unknown. Here, we demonstrate that regulatory T cells (Tregs) compose the main cells expressing the b8 chain of avb8 integrin (Itgb8) in the tumors and that the Itgb8pos Treg population activates TGF-b produced by the cancer cells and stored in the tumor micro-environment. Itgb8 ablation in Tregs impaired TGF-b signaling in T lymphocytes present in the tumor but not in the tumor draining lymph nodes. The cytotoxic function of CD8pos T lymphocytes infiltrating the tumors was subsequently exacerbated leading to an efficient control of the tumor growth. Similar observations were made in patient tumors after anti-Itgb8 antibody treatment. Thus, this study reveals that Tregs work in concert with cancer cells to produce bioactive-TGF-b and create a powerful-immunosuppressive micro-environment.

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BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.021 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i5-i5

Author(s):

Route Pedrosa ◽

Benjamin Schrijver ◽

Rute B Marques ◽

Pieter J M Leenen ◽

Wim A Dik ◽

...

Keyword(s):

Breast Cancer ◽

T Lymphocytes ◽

Brain Metastasis ◽

Brain Metastases ◽

Cancer Cells ◽

Breast Cancer Cells ◽

T Cell Response ◽

Activated T Cells ◽

Breast Cancer Brain Metastasis

Abstract In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.

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Modulation of MUC1 mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes

British Journal of Cancer ◽

10.1054/bjoc.2000.1744 ◽

2001 ◽

Vol 84 (9) ◽

pp. 1258-1264 ◽

Cited By ~ 25

Author(s):

K Kontani ◽

O Taguchi ◽

T Narita ◽

M Izawa ◽

N Hiraiwa ◽

...

Keyword(s):

Breast Cancer ◽

T Lymphocytes ◽

Cancer Cells ◽

Cytotoxic T Lymphocytes ◽

Breast Cancer Cells ◽

Escape Mechanism ◽

Muc1 Mucin

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Methionine-enkephalin secreted by human colorectal cancer cells suppresses T lymphocytes

Cancer Science ◽

10.1111/j.1349-7006.2008.01073.x ◽

2009 ◽

Vol 100 (3) ◽

pp. 497-502 ◽

Cited By ~ 16

Author(s):

Hitoshi Ohmori ◽

Kiyomu Fujii ◽

Tomonori Sasahira ◽

Yi Luo ◽

Mamoru Isobe ◽

...

Keyword(s):

Colorectal Cancer ◽

T Lymphocytes ◽

Cancer Cells ◽

Human Colorectal Cancer ◽

Methionine Enkephalin ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

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Higher human lymphocyte antigen class I expression in early‐stage cancer cells leads to high sensitivity for cytotoxic T lymphocytes

Cancer Science ◽

10.1111/cas.14022 ◽

2019 ◽

Vol 110 (6) ◽

pp. 1842-1852 ◽

Cited By ~ 1

Author(s):

Yu Akazawa ◽

Daisuke Nobuoka ◽

Mari Takahashi ◽

Toshiaki Yoshikawa ◽

Manami Shimomura ◽

...

Keyword(s):

T Lymphocytes ◽

Cancer Cells ◽

Cytotoxic T Lymphocytes ◽

Human Lymphocyte ◽

Early Stage ◽

High Sensitivity ◽

Class I ◽

Early Stage Cancer ◽

Lymphocyte Antigen ◽

Human Lymphocyte Antigen

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Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes

Cancer Immunology Immunotherapy ◽

10.1007/s00262-010-0961-7 ◽

2011 ◽

Vol 60 (4) ◽

pp. 525-535 ◽

Cited By ~ 58

Author(s):

Michael S. Leibowitz ◽

Pedro A. Andrade Filho ◽

Soldano Ferrone ◽

Robert L. Ferris

Keyword(s):

Head And Neck Cancer ◽

T Lymphocytes ◽

Head And Neck ◽

Cancer Cells ◽

Cytotoxic T Lymphocytes ◽

Neck Cancer

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Anticancer and Antioxidant Tannins from Pimenta dioica Leaves

Zeitschrift für Naturforschung C ◽

10.1515/znc-2007-7-811 ◽

2007 ◽

Vol 62 (7-8) ◽

pp. 526-536 ◽

Cited By ~ 40

Author(s):

Mohamed S. A. Marzouk ◽

Fatma A. Moharram ◽

Mona A. Mohamed ◽

Amira M. Gamal-Eldeen ◽

Elsayed A. Aboutabl

Keyword(s):

T Lymphocytes ◽

Cancer Cells ◽

Ellagic Acid ◽

Solid Tumour ◽

2D Nmr ◽

Physicochemical Analysis ◽

The Other ◽

Methyl Gallate ◽

Cytotoxic Compound ◽

Pimenta Dioica

Two galloylglucosides, 6-hydroxy-eugenol 4-O-(6′-O-galloyl)-β-D-4C1-glucopyranoside (4) and 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-2-O-(2′,6′-di-O-galloyl)-β-D-4C1-glucopyranoside (7), and two C-glycosidic tannins, vascalaginone (10) and grandininol (14), together with fourteen known metabolites, gallic acid (1), methyl gallate (2), nilocitin (3), 1-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-(α/β)-d-glucopyranose (5), 4,6-(S)-hexahydroxydiphenoyl-(α/β)-d-glucopyranose (6), 3,4,6-valoneoyl-(α/β)-d-glucopyranose (8), pedunculagin (9), casuariin (11), castalagin (12), vascalagin (13), casuarinin (15), grandinin (16), methyl-flavogallonate (17) and ellagic acid (18), were identified from the leaves of Pimenta dioica (Merr.) L. (Myrtaceae) on the basis of their chemical and physicochemical analysis (UV, HRESI-MS, 1D and 2D NMR). It was found that 9 is the most cytotoxic compound against solid tumour cancer cells, the most potent scavenger against the artificial radical DPPH and physiological radicals including ROO•, OH•, and O2-•, and strongly inhibited the NO generation and induced the proliferation of T-lymphocytes and macrophages. On the other hand, 3 was the strongest NO inhibitor and 16 the highest stimulator for the proliferation of T-lymphocytes, while 10 was the most active inducer of macrophage proliferation.

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Dendritic cells loaded with XAGE-1b protein induce specific antitumor response against lung cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18080 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18080-18080

Author(s):

Q. Zhou ◽

Y. L. Wu ◽

A. L. Guo ◽

K. Wang ◽

C. R. Xu ◽

...

Keyword(s):

Lung Cancer ◽

T Lymphocytes ◽

Cancer Cells ◽

Expression Vector ◽

Normal Lung ◽

Lung Epithelium ◽

Cytotoxic Assay ◽

Antitumor Response ◽

Epithelium Cells

18080 Background: Dendritic cells (DCs) are the most potent antigen-presenting cells for initiating cellular immune response. Cancer-testis antigens (CTA) are the biggest tumor antigens family expressing only in some tumors and genital system but not in normal cells. XAGE-1b gene is one of CTA which highly expresses in lung cancer and has strong immunogenicity. Our study was to examine whether DCs loaded with XAGE-1b protein could induce specific antitumor response against lung cancer cells in vitro. Methods: Tumor tissues and normal lung tissues were obtained by operation from 30 non-small cell lung cancer patients. Cancer cells and normal lung epithelium cells were cultured and saved as target cells. Total RNA were isolated and RT-PCR was done to determine XAGE-1b gene expression. XAGE-1b gene was cloned by constructing expression vector and recombinant protein was expressed and purified by using BL21 (DE3) E. coli and AKTA-FPLC. Peripheral blood monocytes were isolated from 20ml blood and cultured to be DCs in serum-free DCs Medium. DCs were loaded with XAGE-1b protein through coculture and induced T lymphocytes into XAGE-1b-specific cytotoxic T lymphocytes (CTLs). The cytotoxicity of CTLs was then measured by cytotoxic assay. Results: 12/30(40%) lung cancer tissues expressed XAGE-1b gene, most of which were adenocarcinoma (11/12, 91.7%). None of normal tissues expressed it. Gene sequencing and western blot confirmed the expression vector construction and recombinant protein expression. Immunofluorescence identification showed the accumulation of XAGE-1b protein in immature DCs. T lymphocytes were stimulated twice with XAGE-1b protein-loaded DCs. Cytotoxic assay showed that the CTL cytotoxicity was much stronger for XAGE-1b positive tumor cells than for XAGE-1b negative tumor cells and it was almost none for normal lung epithelium cells. Conclusions: Our study indicates that DCs loaded with XAGE-1b protein could induce specific antitumor effect against lung cancer cells in vitro and this model offers a new approach to the immunotherapy for lung cancer. No significant financial relationships to disclose.

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