Immunotherapeutic Potential of B7-DC (PD-L2) Cross-Linking Antibody In Conferring Antitumor Immunity

Radhakrishnan, S.; Nguyen, Huu Lam; Ćirić, Bogoljub; Flies, Dallas B.; Keulen, Virginia P. Van; Tamada, Koji; Chen, Lieping; Rodriguez, Moses; Pease, Larry R.

doi:10.1158/0008-5472.can-03-3025

Cited by 58 publications

(66 citation statements)

References 36 publications

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“…The activated DCs undergo a maturation process that includes loss of their innate ability to acquire exogenous antigens from the environment and induces upregulation of costimulatory molecules that play important roles in the activation of naïve T cells. In contrast, activation of DCs by cross-linking B7-DC did not result in appreciable upregulation of the costimulatory molecule CD86, indicating that the antibody-induced activation profile differs substantially from the activation states induced with TLR or TNF family receptor agonists (14,16). Here, we document key differences in these activation responses and demonstrate that activation after the cross-linking of cell surface B7-DC and activation by treatment with TLR agonists can have synergistic effects on the ability of mice to respond to peptide antigens.…”

Section: B7-dc Cross-linking Restores Antigen Uptake and Augments Antmentioning

confidence: 89%

“…Systemic treatment of mice bearing melanoma lung metastases results in a strong treatment effect, eliminating the tumor nodules in half of the mice and significantly reducing tumor burden in the remaining animals (16). In a model of allergic asthma, treatment of presensitized animals with B7-DC XAb completely blocked the development of airway inflammatory disease (17).…”

Section: B7-dc Cross-linking Restores Antigen Uptake and Augments Antmentioning

confidence: 99%

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RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

Radhakrishnan

Celis

Pease³

2005

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are classified in two states: immature DCs (iDCs), which perform sentinel functions, sampling for antigen and danger signals, and mature DCs (mDCs), which exhibit enhanced antigen-presenting functions but are no longer capable of acquiring antigen. We now describe DCs with a different activation phenotype: cells having the strong antigen-presenting functions of mDCs and the antigen-acquiring functions of iDCs. We have described an antibody that binds the costimulatory molecule B7-DC and activates DCs. The resulting phenotype is distinct from iDCs or mDCs matured by using Toll-like receptor (TLR) agonists. Ability to take up antigen increases, while expression of B71/2 costimulatory and MHC molecules remains unchanged. DCs matured with TLR agonists and then superactivated through B7-DC exhibit a previously unrecognized phenotype. These DCs recover the ability to take up antigen, which is normally lost after treatment with TLR-3 and TLR-9 agonists, yet retain the high expression of costimulatory and MHC molecules and strong antigen-presenting functions of mDCs. Immunization using TLR agonists and B7-DC XAb (cross-linking antibody) together as adjuvant resulted in substantially increased cytolytic T cell responses, particularly when minimal peptide antigens were used. By stimulating DCs with two distinct activation signals, a previously unrecognized phenotype exhibiting augmented antigen-presenting functions was obtained

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Section: B7-dc Cross-linking Restores Antigen Uptake and Augments Antmentioning

confidence: 89%

Section: B7-dc Cross-linking Restores Antigen Uptake and Augments Antmentioning

confidence: 99%

RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

Radhakrishnan

Celis

Pease³

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In this regard we have found that systemic treatment of mice with disseminated B16 melanoma with B7-DC cross-linking Ab protects the animals from the development of lung nodules characteristic of metastasis and leads to their long-term survival (48). Similarly, treatment of mice with 6-day established B16 melanoma grafts completely protects the animals from tumor growth and rapidly induces tumor-specific CTL to melanoma, lymphoma, and breast cancer cell lines (our unpublished observations).…”

Section: Discussionmentioning

confidence: 61%

B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death

Radhakrishnan

Nguyen

Ćirić

et al. 2007

The Journal of Immunology

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Cross-linking cell surface molecules with IgM Abs is a specific approach for activating cells in vitro or in vivo. Dendritic cells (DC) activated with a human B7-DC (PD-L2)-specific IgM Ab can induce strong antitumor responses and block inflammatory airway disease in experimental models, yet the Ab-mediated molecular events promoting these responses remain unclear. Analysis of human or mouse DC treated with the B7-DC cross-linking Ab revealed PI3K-dependent phosphorylation of AKT accompanied by mobilization of NF-κB. Ab-activated DC up-regulated expression of cytokine and chemokine genes in an NF-κB-dependent manner. Importantly, PI3K→AKT→NF-κB activation was found to be indispensable for B7-DC cross-linking Ab-mediated protection of DC from cell death caused by cytokine withdrawal. Although other DC activators similarly protect DC from cell death, a synergy between cross-linking B7-DC and ligating RANK was observed. The parallel signaling events induced in human and mouse DC demonstrate that activation of cells using IgM Ab results in a response governed by a common mechanism and support the hypothesis that B7-DC cross-linking using this Ab may provide beneficial therapeutic immune modulation in human patients similar to those seen in animal models.

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“…This observation suggests the possibility that B7-DC expression on the crosspresenting CD8a À DC might limit CTL generation because upon interaction with PD-1, B7DC has been shown to mediate suppression of CD8 1 T cells [52,53]. However several studies have also indicated an immunostimulatory role for B7-DC in a PD-1 independent manner [54] or following cross-linking with B7-DC specific Ab [55]. Importantly, CD8a À DC have been shown to mediate cross-tolerance to intestinal [56] and keratinocytederived antigens [33], suggesting that cross-presentation by this subset may be associated with the induction of T-cell tolerance, although the role of B7-DC specifically in this process has not been explored.…”

Section: Tdln Cd8amentioning

confidence: 99%

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

et al. 2010

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One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cellassociated tumor antigens to CD8 1 T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c 1 DC. Further analysis revealed that both CD8a 1 and CD8a À DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8a -DC subset. Therefore LN resident CD8a 1 DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses.Key words: Cross-presentation . DC . Membrane antigen . Tumor immunology IntroductionWe have shown in previous studies that cell-associated tumor antigens are cross-presented by host APC to CD8 1 T cells [1][2][3].Despite efficient cross presentation of tumor antigens, only a weak, localized CTL response is induced and this response fails to control tumor growth [1,3,4]. Similarly in patients with cancer, tumor specific CD8 1 T cells, induced spontaneously or in response to therapy, are often detected in the tumor tissue, local draining LN and peripheral blood of cancer patients, without the induction of tumor regression [5,6]. This failure to generate strong CTL responses despite the presentation of the appropriate tumor antigen is perplexing. This lack of an effective anti-tumor CTL response is likely related to the way in which tumor antigens are presented by DC.Evidence from the field of virology, where CTL play a crucial role in controlling viral infection, demonstrates that generation of an effective CTL response requires presentation of viral antigens by activated APC, specifically DC. Notably, in this regard, cancer is generally associated with an environment that does not favor DC activation, indeed, DC found in tumor tissue and local tumordraining LN (TDLN) of cancer patients and tumor-bearing animals display a non-activated phenotype [7,8]. Thus, the manner in which tumor antigens are presented to the immune system, particularly by cross-presenting DC, may be vital in shaping the nature of tumor-specific CD8 1 T-cell responses.Though the contribution of cross-presentation to the generation of anti-tumor immunity has been challenged [9,10], there is convincing evidence that tumor antigens are efficiently crosspresented in vivo [1,[11][12][13]. DC are thought to be the principal cell type responsible for antigen c...

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Immunotherapeutic Potential of B7-DC (PD-L2) Cross-Linking Antibody In Conferring Antitumor Immunity

Cited by 58 publications

References 36 publications

RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

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Immunotherapeutic Potential of B7-DC (PD-L2) Cross-Linking Antibody In Conferring Antitumor Immunity

Cited by 58 publications

References 36 publications

RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

RETRACTED: B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells

B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death

CD8α+ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

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CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor