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1.  TLR4 engagement during TLR3-induced pro-inflammatory signaling in dendritic cells promotes IL-10-mediated suppression of anti-tumor immunity 
Cancer research  2011;71(16):5467-5476.
Toll-like receptor agonists are promising adjuvants for immune therapy of cancer, but their potential efficacy as single or combinatorial agents has yet to be fully evaluated. Here we report that among all TLR agonists tested, dendritic cells (DCs) stimulated with the TLR3 agonist polyI:C displayed the strongest activity in stimulating pro-inflammatory responses and the production of melanoma antigen-specific CD8+ T cells. Simultaneous treatment with TLR7/8 agonists further improved these responses, but the inclusion of bacterial LPS, a TLR4 agonist, suppressed pro-inflammatory cytokine production. This inhibition was contingent upon rapid induction of the suppressive cytokine IL-10 by LPS, leading to dysregulated immune responses and it could be reversed by STAT3 knockdown, p38 blockade or antibodies to IL-10 and its receptor. Our findings show how certain TLR agonist combinations can enhance or limit dendritic cell responses associated with anti-tumor immunity, through their relative ability to induce IL-10 pathways that are immune suppressive.
PMCID: PMC3156386  PMID: 21730023
2.  Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory TH2 cells via an IL-12- and OX40L-dependent pathway 
Cancer cell  2011;19(3):333-346.
Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and over-expressed by many tumors. Here, we documented the presence of MMP-2-specific CD4+ T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4+ T cells displayed an inflammatory TH2 profile, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4+ T cells to differentiate into an inflammatory TH2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type-I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type-2 “conditioner” and may play a role in the observed prevalence of detrimental type-2 responses in melanoma.
Several melanoma-associated antigens have been targeted in immunization strategies to treat melanoma patients. However, the therapeutic efficacy of these approaches remains limited, indicating an urgent need for improvement. Because MMP-2 activity is critical for melanoma progression, it represents an interesting target for vaccine therapy. We show that MMP-2 is an immunogenic tumor antigen. However, MMP-2-specific CD4+ T lymphocytes display a suboptimal inflammatory TH2 profile. MMP-2-conditoned DCs prime TH2 responses against several melanoma-associated antigen (MAA), suggesting that MMP-2 can create a TH2 skewing microenvironment in a bystander fashion. Elucidation of the underlying mechanisms opens the way to improving immune responses towards a more effective TH1 response, and highlights the potential of MMP2 as a target antigen in melanoma.
PMCID: PMC3073826  PMID: 21397857
3.  Dysregulation of anti-tumor immunity by the matrix metalloproteinase-2 
Oncoimmunology  2012;1(1):109-111.
The matrix metalloproteinase-2 (MMP-2), overexpressed in most cancers, induces TH2 polarization by conditioning dendritic cells to over-express OX40L and downregulate IL-12p70 through the degradation of the type-I IFN receptor IFNAR1. Elucidating mechanisms underlying detrimental tumor-associated type-2 responses represent a crucial step in designing effective immune therapies to treat cancer patients.
PMCID: PMC3376966  PMID: 22720227
CD4+ T cell differentiation; CD4+ T cells; dendritic cells; IFNARI; IL-12; matrix metalloproteinase-2; melanoma; OX40L; STAT1
4.  Folding of Matrix Metalloproteinase-2 Prevents Endogenous Generation of MHC Class-I Restricted Epitope 
PLoS ONE  2010;5(7):e11894.
We previously demonstrated that the matrix metalloproteinase-2 (MMP-2) contained an antigenic peptide recognized by a CD8 T cell clone in the HLA-A*0201 context. The presentation of this peptide on class I molecules by human melanoma cells required a cross-presentation mechanism. Surprisingly, the classical endogenous processing pathway did not process this MMP-2 epitope.
Methodology/Principal Findings
By PCR directed mutagenesis we showed that disruption of a single disulfide bond induced MMP-2 epitope presentation. By Pulse-Chase experiment, we demonstrated that disulfide bonds stabilized MMP-2 and impeded its degradation. Finally, using drugs, we documented that mutated MMP-2 epitope presentation used the proteasome and retrotranslocation complex.
These data appear crucial to us since they established the existence of a new inhibitory mechanism for the generation of a T cell epitope. In spite of MMP-2 classified as a self-antigen, the fact that cross-presentation is the only way to present this MMP-2 epitope underlines the importance to target this type of antigen in immunotherapy protocols.
PMCID: PMC2912773  PMID: 20689590
5.  KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity  
The Journal of Clinical Investigation  2008;118(12):3990-4001.
Vaccine strategies that utilize human DCs to enhance antitumor immunity have yet to realize their full potential. Approaches that optimally target a spectrum of antigens to DCs are urgently needed. Here we report the development of a platform for loading DCs with antigen. It is based on killed but metabolically active (KBMA) recombinant Listeria monocytogenes and facilitates both antigen delivery and maturation of human DCs. Highly attenuated KBMA L. monocytogenes were engineered to express an epitope of the melanoma-associated antigen MelanA/Mart-1 that is recognized by human CD8+ T cells when presented by the MHC class I molecule HLA-A*0201. The engineered KBMA L. monocytogenes induced human DC upregulation of costimulatory molecules and secretion of pro-Th1 cytokines and type I interferons, leading to effective priming of Mart-1–specific human CD8+ T cells and lysis of patient-derived melanoma cells. KBMA L. monocytogenes expressing full-length NY-ESO-1 protein, another melanoma-associated antigen, delivered the antigen for presentation by MHC class I and class II molecules independent of the MHC haplotype of the DC donor. A mouse therapeutic tumor model was used to show that KBMA L. monocytogenes efficiently targeted APCs in vivo to induce protective antitumor responses. Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate.
PMCID: PMC2579623  PMID: 19033668
6.  αvβ3-dependent cross-presentation of matrix metalloproteinase–2 by melanoma cells gives rise to a new tumor antigen 
A large array of antigens that are recognized by tumor-specific T cells has been identified and shown to be generated through various processes. We describe a new mechanism underlying T cell recognition of melanoma cells, which involves the generation of a major histocompatibility complex class I–restricted epitope after tumor-mediated uptake and processing of an extracellular protein—a process referred to as cross-presentation—which is believed to be restricted to immune cells. We show that melanoma cells cross-present, in an αvβ3-dependent manner, an antigen derived from secreted matrix metalloproteinase–2 (MMP-2) to human leukocyte antigen A*0201-restricted T cells. Because MMP-2 activity is critical for melanoma progression, the MMP-2 peptide should be cross-presented by most progressing melanomas and represents a unique antigen for vaccine therapy of these tumors.
PMCID: PMC2212908  PMID: 15998788

Results 1-6 (6)