Neuroblastoma-induced inhibition of dendritic cell IL-12 production via abrogation of CD40 expression

Walker, Sonya R.; Redlinger, Richard E.; Barksdale, Edward M.

doi:10.1016/j.jpedsurg.2004.09.050

Cited by 21 publications

(18 citation statements)

References 17 publications

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“…Strome et al [56] reported that DCs pulsed with c-irradiated tumor cells led to effective antigen presentation and antitumor responses in preclinical animal studies. However, we and other investigators demonstrated that pediatric solid tumors, such as NB, inhibit DC maturation both in vivo and in vitro [30,32,35,57,58]. In the current study, we found that high-intensity UV-B induced rapid cell necrosis (not shown).…”

Section: Discussionsupporting

confidence: 45%

“…The mechanisms allowing tumor cells to evade the immune system are varied. Multiple studies have suggested that DC development and maturation are impaired in the presence of advanced solid tumors [30][31][32][33]. The premise behind using DCs to vaccinate patients with cancer is that DCs generated ex vivo, away from the tumor environment, and loaded with antigens would effectively stimulate antitumor immunity [28,[34][35][36].…”

mentioning

confidence: 99%

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Induction of cytolytic T lymphocytes against pediatric solid tumors in vitro using autologous dendritic cells pulsed with necrotic primary tumor

Shilyansky

Jacobs

Doffek

et al. 2007

Journal of Pediatric Surgery

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Section: Discussionsupporting

confidence: 45%

mentioning

confidence: 99%

Induction of cytolytic T lymphocytes against pediatric solid tumors in vitro using autologous dendritic cells pulsed with necrotic primary tumor

Shilyansky

Jacobs

Doffek

et al. 2007

Journal of Pediatric Surgery

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“…Finally, if all the antitumor effects of CD40 were dependent on interaction with CD40L-mediated T cell activation, no antitumor effect would be observed in mice or human subjects lacking (or expressing less) CD40L or expressing nonfunctional mutant CD40L. In addition, impaired antitumor immune responses were associated with reduced expression of CD40L on T cells or CD40 on DC (21)(22)(23). The functional changes that occurred in those DC or T cells due to low CD40 or CD40L expressions are not yet understood.…”

mentioning

confidence: 99%

Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses

Murugaiyan

Agrawal

Mishra

et al. 2007

The Journal of Immunology

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Establishment of host-protective memory T cells against tumors is the objective of an antitumor immunoprophylactic strategy such as reinforcing T cell costimulation via CD40-CD40L interaction. Previous CD40-targeted strategies assumed that T cell costimulation is an all-or-none phenomenon. It was unknown whether different levels of CD40L expression induce quantitatively and qualitatively different effector T cell responses. Using mice expressing different levels of CD40L, we demonstrated that the greater the T cell CD40L expression the less tumor growth occurred; the antitumor T cell response was host-protective. Lower levels of CD40L expression on T cells induced IL-10-mediated suppression of tumor-regressing effector CD8+ T cells and higher productions of IL-4 and IL-10. Using mice expressing different levels of CD40 or by administering different doses of anti-CD40 Ab, similar observations were recorded implying that the induction of protumor or antitumor T cell responses was a function of the extent of CD40 cross-linking. IL-10 neutralization during priming with tumor Ags resulted in a stronger tumor-regressing effector T cell response. Using IL-10−/− DC for priming of mice expressing different levels of CD40L and subsequent transfer of the T cells from the primed mice to nu/nu mice, we demonstrated the protumor role of IL-10 in the induction of tumor-promoting T cells. Our results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.

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“…Furthermore, our data prove that the role of LAG-3 expressed by activated T cells is particularly important in those setting lacking sustained TLR-mediated signaling and when a CD40/CD40L interaction could be of suboptimal intensity, as in the case of an antitumor response (7)(8)(9).…”

Section: Discussionmentioning

confidence: 55%

“…Moreover, it has been shown that strong and sustained CD40 signaling is required to enable DC to release cytokines while weak and transient receptor activation results only into phenotypic up-regulation of cell surface activation markers (6). In several pathologic conditions such as in tumors, CD40/CD40L signaling is limited or impaired (7,8) and a suboptimal triggering of this DC activation pathway may elicit an IL-10-predominant response hampering the on setting of host-protective, memory T cells (9). In the absence of the exogenous TLR agonist, such as in the case of an antitumor response, there is therefore the need to integrate the weak CD40/CD40L signaling to achieve optimal DC activation.…”

mentioning

confidence: 99%

Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

Casati¹,

Camisaschi²,

Novellino³

et al. 2008

The Journal of Immunology

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Data have been reported on the in vivo adjuvant role of soluble lymphocyte activation gene-3 (LAG-3) recombinant protein in mouse models and on its ability to support the in vitro generation of human, tumor-specific CTLs. In this study, we show that soluble human rLAG-3 protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promoted the production of chemokines and TNF-α inflammatory cytokine. When given in association with optimal or suboptimal doses of CD40/CD40L, hLAG-3Ig functions as a strong costimulatory factor and induces full functional activation of monocyte-derived dendritic cells that includes the production of high level of IL-12p70. Moreover, evidence is here provided that this costimulatory function licensing dendritic cells to produce IL-12p70 is also a functional property of LAG-3 molecules when expressed in a physiological context by CD4+ activated T cells. Altogether, these data show for the first time a role of LAG-3 in mediating dendritic cell activation when expressed on the T cell surface or released after specific Ag stimulation in the interspaces of immunological synapses.

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Neuroblastoma-induced inhibition of dendritic cell IL-12 production via abrogation of CD40 expression

Cited by 21 publications

References 17 publications

Induction of cytolytic T lymphocytes against pediatric solid tumors in vitro using autologous dendritic cells pulsed with necrotic primary tumor

Induction of cytolytic T lymphocytes against pediatric solid tumors in vitro using autologous dendritic cells pulsed with necrotic primary tumor

Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses

Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

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