Rapid High Efficiency Sensitization of CD8+ T Cells to Tumor Antigens by Dendritic Cells Leads to Enhanced Functional Avidity and Direct Tumor Recognition Through an IL-12-Dependent Mechanism

(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.

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Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain

Journal of Experimental Medicine ◽

10.1084/jem.20082487 ◽

2009 ◽

Vol 206 (2) ◽

pp. 463-475 ◽

Cited By ~ 99

Author(s):

Jürgen Kuball ◽

Beate Hauptrock ◽

Victoria Malina ◽

Edite Antunes ◽

Ralf-Holger Voss ◽

...

Keyword(s):

T Cells ◽

Structural Changes ◽

Tumor Antigens ◽

Cell Receptor ◽

Temperature Dependent ◽

Functional Avidity ◽

Surface Molecules ◽

Glycosylation Sites ◽

Potential Strategy ◽

Dependent Mechanism

Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512–519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR α or β chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (ΔTCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or ΔTCR chains bound tetramer equivalently at 4°C, but tetramer binding was enhanced at 37°C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.

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Concurrent delivery of tumor antigens and activation signals to dendritic cells by irradiated CD40 ligand-transfected tumor cells resulted in efficient activation of specific CD8+ T cells

Cancer Gene Therapy ◽

10.1038/sj.cgt.7700663 ◽

2003 ◽

Vol 11 (2) ◽

pp. 135-147 ◽

Cited By ~ 11

Author(s):

Ko-Jiunn Liu ◽

Li-Fan Lu ◽

Hui-Ting Cheng ◽

Yi-Mei Hung ◽

Sheng-Ru Shiou ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Tumor Cells ◽

Cd8 T Cells ◽

Tumor Antigens ◽

Cd40 Ligand

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Cross-Priming of Naive Cd8 T Cells against Melanoma Antigens Using Dendritic Cells Loaded with Killed Allogeneic Melanoma Cells

Journal of Experimental Medicine ◽

10.1084/jem.192.11.1535 ◽

2000 ◽

Vol 192 (11) ◽

pp. 1535-1544 ◽

Cited By ~ 207

Author(s):

Frederic Berard ◽

Patrick Blanco ◽

Jean Davoust ◽

Eve-Marie Neidhart-Berard ◽

Mahyar Nouri-Shirazi ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Tumor Antigens ◽

Cytotoxic T Lymphocyte ◽

Melanoma Cells ◽

Autologous Tumor ◽

Multiple Tumor ◽

Melanoma Antigens

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201− melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.

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