Targeting Apoptotic Tumor Cells to FcγR Provides Efficient and Versatile Vaccination Against Tumors by Dendritic Cells

Akiyama, Kenichi; Ebihara, Shin; Yada, Ayumi; Matsumura, K.; Aiba, Setsuya; Nukiwa, Toshihiro; Takai, Toshiyuki

doi:10.4049/jimmunol.170.4.1641

Cited by 94 publications

(92 citation statements)

References 30 publications

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“…In addition, even when an attempt was made to increase protein uptake by the target cells, by forming immunocomplexes with specific antibody, there was no HTL proliferation to the PAX3/FKHR-loaded APC. This strategy of increasing protein uptake has proven to be effective in other studies [26,27]. And last, given the low concentration of peptide needed to stimulate HTL proliferation the lack of PAX3/FKHR protein in tumor cells most likely was not an issue in these experiments.…”

Section: Discussionmentioning

confidence: 91%

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Lack of effective T-lymphocyte response to the PAX3/FKHR translocation area in alveolar rhabdomyosarcoma

Rodeberg

Nuss

Heppelmann

et al. 2004

Cancer Immunol Immunother

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Purpose-Alveolar rhabdomyosarcoma (ARMS) frequently contains the fusion transcription factor PAX3/FKHR. Therefore, clinical studies have been initiated to utilize the PAX3/FKHR translocation point area as a peptide vaccine against ARMS. Our study was directed at identifying antigenic T-lymphocyte epitopes at the PAX3/FKHR translocation point area.Experimental design-The peptide sequence surrounding the PAX3/FKHR translocation point was evaluated by MHC binding algorithms for potential T-lymphocyte antigenic epitopes (class I molecules HLA-A1, -A2 and -A3; class II molecules HLA-DR1, -DR4 and -DR7). Using in vitro techniques, dendritic cells loaded with PAX3/FKHR peptides were used to stimulate na¿ve Tlymphocytes. T-lymphocyte activity was then evaluated by 51 Cr release and 3 H-thymidine uptake assays.Results-Only one HLA-A3-restricted epitope was predicted by the algorithms. The peptide was prepared and tested for its ability to stimulate na¿ve cytotoxic T-lymphocytes (CTLs). Unfortunately, the peptide was unsuccessful at stimulating na¿ve CTL. However, induction of na¿ve helper Tlymphocytes (HTL) to recognize and respond to the PAX3/FKHR translocation peptide was successful. Yet, this HTL peptide activity did not translate into recognition of PAX3/FKHRcontaining ARMS tumor cells.Conclusions-It appears that the fusion area of PAX3/FKHR may not be a good source of antigenic anti-tumor peptide epitopes. These results raise serious concerns about the success and applicability of future peptide-based vaccine immunotherapy directed at the PAX3/FKHR translocation point.

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Section: Discussionmentioning

confidence: 91%

“…5a). It has previously been demonstrated that incubating protein with an appropriate antibody can increase its uptake into PBMC [26,27]. The PAX3/FKHR vector contains a HIS tag.…”

Section: Htl Recognition Of Tumor and Pax3/fkhr Proteinmentioning

confidence: 99%

Lack of effective T-lymphocyte response to the PAX3/FKHR translocation area in alveolar rhabdomyosarcoma

Rodeberg

Nuss

Heppelmann

et al. 2004

Cancer Immunol Immunother

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“…Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG augments DC maturation, leading to efficient antigen presentation [18][19][20]. On the other hand, the inhibitory receptors harbor ITIM in their cytoplasmic portions and initiate inhibitory signaling by recruiting protein phosphatases, such as SHP-1 or SHIP, to phosphotyrosylated ITIM [13].…”

Section: Introductionmentioning

confidence: 99%

“…augments DC maturation, leading to efficient antigen presentation [18][19][20]. On the other hand, the inhibitory receptors harbor ITIM in their cytoplasmic portions and initiate inhibitory signaling by recruiting protein phosphatases, such as SHP-1 or SHIP, to phosphotyrosylated ITIM [13].…”

mentioning

confidence: 99%

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

et al. 2008

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Dendritic cells (DC) play pivotal roles in the induction and regulation of both innate and acquired immunity. DC express several cell-surface immune inhibitory receptors. However, little is known about their potential immunoregulatory functions in the context of T-cell activation. Here we report that murine gp49B, a member of the immunoglobulin superfamily, harboring immunoreceptor tyrosine-based inhibitory motifs, is expressed on DC and downregulates cellular activity to prevent the excessive activation of T cells in vitro and in vivo. Bone marrow-derived DC (BMDC) from newly generated gp49B-deficient (gp49B À/À ) mice induced enhanced proliferation and IL-2 release of antigen-specific CD4 1 and CD8 1 T cells compared with BMDC from wild-type mice, in a cell-cell contact manner. The enhanced proliferation by gp49B À/À BMDC was also observed in allogeneic CD4 1 and CD8 1 T cells. Moreover, the transfer of allogeneic BALB/c splenocytes into C57BL/6 gp49B À/À mice induced severe acute graft-versus-host disease with an augmented upregulation of CD86 on CD11c 1 splenic gp49B À/À DC, while transfer of C57BL/6 gp49B À/À splenocytes into BALB/c mice did not, suggesting the exacerbation of the disease was due, at least in part, to augmented activation of recipient gp49B À/À DC. These findings demonstrate a novel regulatory role of gp49B in the function of DC.Key words: Antigen presentation Á Costimulation Á DC Á Regulatory receptor Á Tolerance IntroductionDendritic cells (DC) are professional antigen-presenting cells that recognize a diverse repertoire of antigens and present them to naïve T cells for the induction of acquired immunity [1]. DC are also related to innate immunity by producing cytokines such as both type I and II IFN, or by activating NK cells [2,3]. In addition, recent reports revealed that a subset of DC maintains peripheral tolerance in the steady state [4], showing that DC play a pivotal role in the induction of immune responses including autoimmunity.On the DC surface, a variety of structurally different immunoreceptors that regulate DC and T-cell functions have been found, including CD80, CD86, CD40, and various Ig superfamily and lectin family molecules [5]. Among them, a group of paired Ig superfamily receptors, termed Ig-like receptors, have been attracting the interest of many researchers because they are expressed on various subsets of DC and are considered to contribute to the development or activation of DC [6][7][8][9][10]. Generally, Ig-like receptors are subdivided into two types, namely activating and inhibitory receptors, and in some cases they are expressed on hematopoietic cells in a pair-wise manner [11][12][13][14]. Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG 2426augments DC maturation, leading to efficient antigen presentation [18...

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“…There are s en DNA or m mplexes [8][9][10] or Cs by immatur l because they e antigen analy unknown num riginal immuni s is safe (elicit nity" [3] . Furthe ainst numerous ociated antigen age could comp [16,23] .…”

Section: Introductionmentioning

confidence: 99%

Antibody opsonization of tumor cell membranes using hapten-PEG-lipid conjugates

Sugiura

Kato

Nagamune

2015

JBEI

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Dendritic cell (DC) immunotherapy is a newly developed type of tumor immunotherapy. As a method for generating antigen-presenting DCs, the phagocytosis of whole tumor cells (WTCs) opsonized with antibodies by DCs (antibody-dependent cellular phagocytosis, ADCP) is especially efficient. To opsonize tumor cells, tumor-specific antibodies are usually required. Therefore conventional ADCP was limited to tumor types for which antigens have been identified and antigen-specific antibodies are available. Herein, we developed a general method to promote ADCP by DCs using an arbitrary antibody and evaluated its antitumor effects. To opsonize tumor cells with a tumor-nonspecific antibody, we modified tumor cell surfaces with PEG-lipid-hapten conjugates and a conjugated anti-hapten antibody. By co-culturing DCs with the antibody-opsonized tumor cells, the phagocytosis and DC maturation rates were enhanced by ~20% and ~10%, respectively, compared with co-cultured non-opsonized tumor cells. The administration of tumor antigen-loaded matured DCs to mice resulted in enhanced tumor rejection and long-term survival. The advantages of this method are that tumor-specific antibodies are not required and DCs can present uncharacterized antigens by phagocytosing WTCs and associated antigens. Therefore, this method might be applicable to various types of tumors for which specific antigens have not yet been identified.

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Targeting Apoptotic Tumor Cells to FcγR Provides Efficient and Versatile Vaccination Against Tumors by Dendritic Cells

Cited by 94 publications

References 30 publications

Lack of effective T-lymphocyte response to the PAX3/FKHR translocation area in alveolar rhabdomyosarcoma

Lack of effective T-lymphocyte response to the PAX3/FKHR translocation area in alveolar rhabdomyosarcoma

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Antibody opsonization of tumor cell membranes using hapten-PEG-lipid conjugates

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