Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

Institut de Sciences et Technologies du Medicament de Toulouse, CNRS-Pierre Fabre, Toulouse, France.
Cancer Gene Therapy (Impact Factor: 2.42). 12/2006; 13(11):1002-10. DOI: 10.1038/sj.cgt.7700974
Source: PubMed

ABSTRACT The HER-2/Neu oncogene has been implicated in human and mouse breast cancer. Indeed, transgenic MMTV-neu mice expressing this oncogene from the mammary tumor virus long terminal repeat develop spontaneous mammary tumors and die within 1 year of life. We have expressed the class II transactivator (CIITA) and/or the costimulatory molecule CD80 (B7.1) in a mammary carcinoma cell line (MCNeuA) derived from these mice. Class II transactivator directs the expression of MHC class II and the machinery for antigen processing and presentation by this pathway. When injected into MMTV-neu mice, tumor cells expressing CD80 or CD80 and CIITA, were rejected completely. In addition, following the rejection of dual expressing cells, 75% of the mice were protected against the development of subsequent spontaneous tumors. Cells expressing only CD80 or CIITA were not as effective as antitumor vaccines in preventing the development of spontaneous tumors. Thus, converting cancer cells into antigen presenting cells could represent an effective immunotherapy for breast cancer.

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Available from: Michael Campbell, Apr 14, 2014
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    • "DC loaded with TAAs have been also used with the aim of providing a direct source of ready-to-use MHC-II–tumor peptide complexes for optimal priming and triggering of TH cells (24, 25) and recent clinical results in melanoma patients give further hope in improving clinical responses by this approach (26). Several groups, including ours, have instead investigated the possibility to render tumor cells themselves MHC class II-positive and thus used them as potential surrogate APC for triggering tumor-specific TH cells (27–29). Within this frame, two distinct approaches have been described. "
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    ABSTRACT: Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.
    Frontiers in Oncology 02/2014; 4:32. DOI:10.3389/fonc.2014.00032
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    • "MHC class II positive tumor cells are also effective APCs in vivo and can present novel endogenous antigenic peptides not presented by host APCs [5]. Furthermore, transfection of tumors with class II transactivator (CIITA) elicits MHC class II expression and can restore the ability of certain tumor cells to present antigen and induce immunity [9,10]. Although cross-presentation is the major mechanism generating immunity [2,3], the above studies on tumors as APC suggest that, at least in certain tumors, direct antigen presentation could provide an alternative or additional pathway in tumor immunity. "
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    ABSTRACT: Numerous immune genes are epigenetically silenced in tumor cells and agents such as histone deacetylase inhibitors (HDACi), which reverse these effects, could potentially be used to develop therapeutic vaccines. The conversion of cancer cells to antigen presenting cells (APCs) by HDACi treatment could potentially provide an additional pathway, together with cross-presentation of tumor antigens by host APCs, to establish tumor immunity. HDACi-treated B16 melanoma cells were used in a murine vaccine model, lymphocyte subset depletion, ELISpot and Cytotoxicity assays were employed to evaluate immunity. Antigen presentation assays, vaccination with isolated apoptotic preparations and tumorigenesis in MHC-deficient mice and radiation chimeras were performed to elucidate the mechanisms of vaccine-induced immunity. HDACi treatment enhanced the expression of MHC class II, CD40 and B7-1/2 on B16 cells and vaccination with HDACi-treated melanoma cells elicited tumor specific immunity in both prevention and treatment models. Cytotoxic and IFN-gamma-producing cells were identified in splenocytes and CD4+, CD8+ T cells and NK cells were all involved in the induction of immunity. Apoptotic cells derived from HDACi treatments, but not H2O2, significantly enhanced the effectiveness of the vaccine. HDACi-treated B16 cells become APCs in vitro and studies in chimeras defective in cross presentation demonstrate direct presentation in vivo and short-term but not memory responses and long-term immunity. The efficacy of this vaccine derives mainly from cross-presentation which is enhanced by HDACi-induced apoptosis. Additionally, epigenetic activation of immune genes may contribute to direct antigen presentation by tumor cells. Epigenetically altered cancer cells should be further explored as a vaccine strategy.
    Journal of Translational Medicine 02/2007; 5(1):64. DOI:10.1186/1479-5876-5-64 · 3.93 Impact Factor
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    ABSTRACT: This paper reports the implementation and calibration of a microscopic three-electrode electrochemical sensor integrated with a polydimethylsiloxane (PDMS) microchannel to form a rapid prototype chip technology that is used to develop sensing modules for biomolecular signals. The microfluidic/microelectronic fabrication process yields identical, highly uniform, and geometrically well-defined microelectrodes embedded in a microchannel network. Each three-microelectrode system consists of a Au working electrode with a nominal surface area of 9 mum<sup>2</sup>, a Cl<sub>2</sub> plasma-treated Ag/AgCl reference electrode, and a Au counter electrode. The patterned electrodes on the glass substrate are aligned and irreversibly bonded with a PDMS microchannel network giving a channel volume of 72 nL. The electrokinetic properties and the diffusion profile of the microchannels are investigated under electrokinetic flow and pressure-driven flow conditions. Cyclic voltammetry of 10 mM K<sub>3 </sub>Fe(CN)<sub>6</sub> in 1 M KNO<sub>3</sub> demonstrates that the electrode responses in the cell are characterized by linear diffusion. The voltammograms show that the system is a quasi-reversible redox process, with heterogeneous rate constants ranging from 3.11 to 4.94times10<sup>-3</sup> cm/s for scan rates of 0.1-1 V/s. The current response in the cell is affected by the adsorption of the electroactive species on the electrode surface. In a low-current DNA hybridization detection experiment, the electrode cell is modified with single-stranded thiolated DNA. The electrocatalytic reduction of 27 muM Ru(NH<sub>3</sub>)<sub>6</sub> <sup>3+</sup> in a solution containing 2 mM Fe(CN)<sub>6</sub> <sup>3-</sup> is measured before and after the exposure of the electrode cell to a 500-nM target DNA sample. The preliminary result showing an increase in the peak current response demonstrates the hybridization-based detection of a complementary target DNA sequence
    IEEE Sensors Journal 01/2007; 6(6-6):1395 - 1402. DOI:10.1109/JSEN.2006.884444 · 1.76 Impact Factor
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