Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine

The capacity of cytotoxic-T lymphocytes to recognize and destroy tumor cells depends on the surface expression by tumor cells of MHC class I molecules loaded with tumor antigen peptides. Loss of MHC-I expression is the most frequent mechanism by which tumor cells evade the immune response. The restoration of MHC-I expression in cancer cells is crucial to enhance their immune destruction, especially in response to cancer immunotherapy. Using mouse models, we recovered MHC-I expression in the MHC-I negative tumor cell lines and analyzed their oncological and immunological profile. Fhit gene transfection induces the restoration of MHC-I expression in highly oncogenic MHC-I-negative murine tumor cell lines and genes of the IFN-γ transduction signal pathway are involved. Fhit-transfected tumor cells proved highly immunogenic, being rejected by a T lymphocyte-mediated immune response. Strikingly, this immune rejection was more frequent in females than in males. The immune response generated protected hosts against the tumor growth of non-transfected cells and against other tumor cells in our murine tumor model. Finally, we also observed a direct correlation between FHIT expression and HLA-I surface expression in human breast tumors. Recovery of Fhit expression on MHC class I negative tumor cells may be a useful immunotherapeutic strategy and may even act as an individualized immunotherapeutic vaccine.

Download Full-text

Multiple Myeloma as Target for γδ T Cell Mediated Immunotherapy - Expression of the Putative Vγ9Vδ2-TCR Ligand F1-ATPase on Myeloma Cells.

Blood ◽

10.1182/blood.v106.11.3391.3391 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3391-3391

Author(s):

Volker Kunzmann ◽

Judith Engert ◽

Brigitte Kimmel ◽

Martin Wilhelm ◽

Hermann Einsele

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Surface Expression ◽

Tumor Cell Lines ◽

Myeloma Cells ◽

F1 Atpase ◽

Vγ9vδ2 T Cells

Abstract Activated Vγ9Vδ2 T cells, the major γδ T lymphocyte subset in humans, show cytolytic activity against various tumor cells. However, tumor antigens recognized by the TCR remained unkown so far. Recently, the ectopic surface expression of the F1-ATPase, normally expressed on the internal membrane of mitochondria, was implicated in tumor recognition of Vγ9Vδ2 T cells (Scotet E. et al., Immunity2005; 22:71–80). Surface expression of the a chain of the F1-ATPase (recognized by monoclonal antibody 7H10) strongly correlates with susceptibility of tumor cells against Vγ9Vδ2 T cell lysis. Different functions have been attributed to the ectopic expression of the F1-ATPase on the cell surface, including an immunoregulatory role induced by cell stress, receptor for angiostatin or regulation of lipoprotein transport through high-affinity apolipoprotein A-I binding. In this study we evaluated the surface expression of this F1-ATPase on hematopoetic tumor cell lines and on primary tumor cells from hematological malignancies. As already shown, the a subunit of F1-ATPase was clearly detected on several tumor cell lines which are consistently killed by activated Vγ9Vδ2 T cells (Daudi, K562, RPMI 8226), whereas the known Vγ9Vδ2 T cell resistant tumor cell lines (Raji, Jurkat) did not express detectable levels of the F1-ATPase. Analysis of 42 primary hematopoetic tumor cells (21 myeloma, 17 AML, 4 B-NHL) revealed frequent expression of F1-ATPase on primary myeloma cells (14/19 positive), whereas primary AML blasts (3/17 positive) and primary NHL cells (1/4 positive) expressed the putative Vγ9Vδ2-TCR ligand F1-ATPase less frequently. To further evaluate the functional role of F1-ATPase expression in Vγ9Vδ2 T cell mediated recognition of myeloma cells, cytotoxicity assays were performed. The mAb against the a subunit of F1-ATPase significantly decreased in vitro lysis of myeloma cells lines and primary myeloma cells by activated Vγ9Vδ2 T cells. These results suggests Vγ9Vδ2 TCR-dependent interactions between myeloma cells and Vγ9Vδ2 T cells and indicate that multiple myeloma should be considered as a major target for γδ T-cell mediated immunotherapy.

Download Full-text

Diversity of the cytotoxic melanoma-specific immune response: Some CTL recognize autologous fresh tumor cells and not tumor cell lines

Immunology Letters ◽

10.1016/s0165-2478(97)87694-8 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 214

Author(s):

E Dufour

Keyword(s):

Immune Response ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Specific Immune Response ◽

Tumor Cell Lines

Download Full-text

Diversity of the cytotoxic melanoma-specific immune response: Some CTL recognize autologous fresh tumor cells and not tumor cell lines

Immunology Letters ◽

10.1016/s0165-2478(97)85856-7 ◽

1997 ◽

Vol 56 ◽

pp. 214 ◽

Cited By ~ 1

Author(s):

E. Dufour ◽

C. Flament ◽

G. Carcelain ◽

C. Gaudin ◽

V. Scott ◽

...

Keyword(s):

Immune Response ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Specific Immune Response ◽

Tumor Cell Lines

Download Full-text

Interaction of Human Tumor Cells with Human Platelets and the Coagulation System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665296 ◽

1983 ◽

Vol 50 (03) ◽

pp. 726-730 ◽

Cited By ~ 11

Author(s):

Hamid Al-Mondhiry ◽

Virginia McGarvey ◽

Kim Leitzel

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Human Tumor ◽

Human Platelets ◽

Factor Vii ◽

Coagulation System ◽

Breast Adenocarcinoma ◽

Activate Factor ◽

Tumor Cell Lines

SummaryThis paper reports studies on the interaction between human platelets, the plasma coagulation system, and two human tumor cell lines grown in tissue culture: Melanoma and breast adenocarcinoma. The interaction was monitored through the use of 125I- labelled fibrinogen, which measures both thrombin activity generated by cell-plasma interaction and fibrin/fibrinogen binding to platelets and tumor cells. Each tumor cell line activates both the platelets and the coagulation system simultaneously resulting in the generation of thrombin or thrombin-like activity. The melanoma cells activate the coagulation system through “the extrinsic pathway” with a tissue factor-like effect on factor VII, but the breast tumor seems to activate factor X directly. Both tumor cell lines activate platelets to “make available” a platelet- derived procoagulant material necessary for the conversion of prothrombin to thrombin. The tumor-derived procoagulant activity and the platelet aggregating potential of cells do not seem to be inter-related, and they are not specific to malignant cells.

Download Full-text

Molecular analysis of MHC-class-I alterations in human tumor cell lines

International Journal of Cancer ◽

10.1002/ijc.2910470723 ◽

1991 ◽

Vol 47 (S6) ◽

pp. 123-130 ◽

Cited By ~ 16

Author(s):

Francisco Ruiz-Cabello ◽

Millán Perez-Ayala ◽

Ovidio Gomez ◽

Maximino Redondo ◽

Angel Concha ◽

...

Keyword(s):

Tumor Cell ◽

Mhc Class I ◽

Cell Lines ◽

Molecular Analysis ◽

Human Tumor ◽

Class I ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

Download Full-text

Establishment of Tumor Cell Lines: From Primary Tumor Cells to a Tumor Cell Line

Cell Culture Technology - Learning Materials in Biosciences ◽

10.1007/978-3-319-74854-2_4 ◽

2018 ◽

pp. 61-73

Author(s):

Katharina Meditz ◽

Beate Rinner

Keyword(s):

Tumor Cell ◽

Cell Line ◽

Tumor Cells ◽

Cell Lines ◽

Primary Tumor ◽

Tumor Cell Line ◽

Tumor Cell Lines

Download Full-text

A Nuclear-Directed Ribonuclease Variant Targets Cancer Stem Cells and Inhibits Migration and Invasion of Breast Cancer Cells

Cancers ◽

10.3390/cancers13174350 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4350

Author(s):

Jessica Castro ◽

Giusy Tornillo ◽

Gerardo Ceada ◽

Beatriz Ramos-Neble ◽

Marlon Bravo ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Cell ◽

Cancer Cells ◽

Tumor Cells ◽

Cell Lines ◽

Breast Cancer Cells ◽

Migration And Invasion ◽

Tumor Cell Lines

Despite the significant advances in cancer research made in recent years, this disease remains one of the leading causes of death worldwide. In part, this is due to the fact that after therapy, a subpopulation of self-renewing tumor cells can survive and promote cancer relapse, resistance to therapies and metastasis. Targeting these cancer stem cells (CSCs) is therefore essential to improve the clinical outcome of cancer patients. In this sense, multi-targeted drugs may be promising agents targeting CSC-associated multifocal effects. We have previously constructed different human pancreatic ribonuclease (RNase) variants that are cytotoxic for tumor cells due to a non-classical nuclear localization signal introduced in their sequence. These cytotoxic RNases affect the expression of multiple genes involved in deregulated metabolic and signaling pathways in cancer cells and are highly cytotoxic for multidrug-resistant tumor cell lines. Here, we show that these cytotoxic nuclear-directed RNases are highly selective for tumor cell lines grown in 3D, inhibit CSCs’ development and diminish the self-renewal capacity of the CSCs population. Moreover, these human RNase variants reduce the migration and invasiveness of highly invasive breast cancer cells and downregulate N-cadherin expression.

Download Full-text

HLA-E surface expression is independent of the availability of HLA class I signal sequence-derived peptides in human tumor cell lines

Human Immunology ◽

10.1016/j.humimm.2004.10.006 ◽

2005 ◽

Vol 66 (1) ◽

pp. 1-12 ◽

Cited By ~ 29

Author(s):

Giulio Lelio Palmisano ◽

Elisabetta Contardi ◽

Anna Morabito ◽

Vittoria Gargaglione ◽

Giovanni Battista Ferrara ◽

...

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Signal Sequence ◽

Human Tumor ◽

Hla Class I ◽

Surface Expression ◽

Class I ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

Download Full-text

Breast Tumor Cell Lines From Pleural Effusions2

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/53.3.661 ◽

1974 ◽

Vol 53 (3) ◽

pp. 661-674 ◽

Cited By ~ 562

Author(s):

R. Cailleau ◽

R. Young ◽

M. Olivé ◽

W. J. Reeves

Keyword(s):

Chromosome Number ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Breast Tumor ◽

Tumor Cell Lines ◽

Breast Cancer Patients ◽

Pleural Effusions ◽

Epithelial Tumor

Summary During 1973, 4 new epithelial tumor cell lines were isolated from pleural effusions from breast cancer patients. We describe 3 of these lines: MDA-MB-134, with a mean chromosome number of 43; MDA-MB-175, with a mean chromosome number of 49; and MDA-MB-231, with a mean chromosome number between 65 and 69. We isolated the same cell type from 4 of 10 effusions from MDA-MB-134 and from 6 of 8 effusions from MDA-MB-175. We found that pleural effusions as a source of breast tumor cells to be cultured and studied in vitro have the following advantages: 1) large amounts of material and the possibility of obtaining sequential samples from the same patient; 2) high viability of tumor cells; 3) scarcity or absence of fibroblasts; and 4) the possibility of separating the tumor cells from other “contaminating” cell types by differences in their speed or degree of attachment to the flask. All lines from different patients differed, as seen grossly and microscopically. All lines from sequential pleural effusions from the same patient were apparently alike. No viruses or mycoplasmas were detected in any line.

Download Full-text