Chemotherapeutic Agents in Noncytotoxic Concentrations Increase Antigen Presentation by Dendritic Cells via an IL-12-Dependent Mechanism

Department of Pathology, University of Pittsburgh Medical Center, PA 15213, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2009; 183(1):137-44. DOI: 10.4049/jimmunol.0900734
Source: PubMed


Antineoplastic chemotherapeutic agents may indirectly activate dendritic cells (DCs) by inducing the release of "danger" signals from dying tumor cells. Whereas the direct cytotoxic or inhibitory effect of conventional chemotherapy on DCs has been reported, modulation of DC function by chemotherapeutic agents in low noncytotoxic concentrations has not yet been investigated. We have tested the effects of different classes of antineoplastic chemotherapeutic agents used in low noncytotoxic concentrations on the Ag-presenting function of DCs. We revealed that paclitaxel, doxorubicin, mitomycin C, and methotrexate up-regulated the ability of DCs to present Ags to Ag-specific T cells. Stimulation of DC function was associated with the up-regulation of expression of Ag-processing machinery components and costimulatory molecules on DCs, as well as increased IL-12p70 expression. However, the ability of DCs treated with paclitaxel, methotrexate, doxorubicin, and vinblastine to increase Ag presentation to Ag-specific T cells was abolished in DCs generated from IL-12 knockout mice, indicating that up-regulation of Ag presentation by DCs is IL-12-dependent and mediated by the autocrine or paracrine mechanisms. At the same time, IL-12 knockout and wild-type DCs demonstrated similar capacity to up-regulate OVA presentation after their pretreatment with low concentrations of mitomycin C and vincristine, suggesting that these agents do not utilize IL-12-mediated pathways in DCs for stimulating Ag presentation. These findings reveal a new mechanism of immunopotentiating activity of chemotherapeutic agents-a direct immunostimulatory effect on DCs (chemomodulation)-and thus provide a strong rationale for further assessment of low-dose chemotherapy given with DC vaccines for cancer treatment.

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Available from: Michael R. Shurin
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    • "©Youth Education and Research Trust (YERT) Mahmood et al., 2015 The results demonstrated that doxorubicin, methotrexate, vinblastine and paclitaxel used IL-12 dependent pathway whereas mitomycin C and vincristine used IL-12 independent pathway for up regulation of DC activity to present antigen to Ag-specific T cells (Shurin et al., 2009). Michels et al. (2012), proposed another mechanism for immunomodulation by intermolecular interaction between chemo drug paclitaxel and myeloid derived suppressor cells (MDSC). "
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    ABSTRACT: Dendritic cells (DCs) have been tested for cancer immunotherapy over the past two decades in different clinical trials. During this period, efforts were put forth to optimize different parameters influencing the anti-tumor efficacy of ex-vivo generated DCs including maturation stimuli, antigen source, route of vaccine administration and adjuvant usage. In a recent paradigm shift, combinatorial therapy has emerged as possible answer to improve the efficacy of DC vaccines. Specifically, chemotherapy is reported to be associated with synergistic effects with DCs by altering the innate and adaptive arms of immune system. Chemotherapeutic drugs promote the molecular rearrangement on apoptotic tumor cells rendering them to be recognized by phagocytic DCs. The phagocytosis of immunogenic tumor cells results in maturation of DCs leading to an effective antitumor response. While the tumor suppressive microenvironment is subverted, the actions of chemo drugs also stimulate the immune effector cells either directly or indirectly by causing the release of cytokines. Here, we reviewed the assessment of the clinical development in DC vaccine trials and focused on combinatorial approaches using chemo drugs while understanding molecular mechanism underlying the interactions between anti-neoplastic drugs and immune cells.
    Full-text · Article · May 2015
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    • "In view of these undesirable toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression [21]. For instance, it has been recently reported that Pac in low and ultra low doses directly stimulates activity of immune effector cells, increases their ability to recognize cancerous cells [22], [23], and up-regulates the efficacy of anticancer immunotherapy in vivo [24]. Interestingly, Pac in ultra low doses may also decrease the number and activity of immunosuppressive immune regulatory cells both in vivo and in vitro [25], [26]. "
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    ABSTRACT: Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Ret cells established from skin melanoma of transgenic mice were incubated with 5 or 10 mM of CP for 24 hours. DCs were generated from the BM of normal mice as described (Shurin et al, 2009). Before co-incubation with DCs, CP-treated Ret cells were washed twice. "
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    ABSTRACT: Low-dose cyclophosphamide (CP) therapy induces immunogenic tumor cell death and decreases regulatory T cell (Treg) numbers in mice with transplantable tumors. Using the ret transgenic murine melanoma model that resembles human melanoma, we detected no beneficial antitumor effects with such treatment, despite a decrease in Tregs. On the contrary, low-dose CP enhanced the production of chronic inflammatory mediators in melanoma lesions associated with increased accumulation of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), which exhibit elevated suppressive activity and nitric oxide (NO) production as well as inhibition of T-cell proliferation. Moreover, the frequencies of CD8(+) T cells in the tumors and their ability to produce perforin were decreased. To study whether the observed CP-induced MDSC expansion and activation also occurs under chronic inflammatory tumor-free conditions, mice exhibiting chronic inflammation were treated with CP. Similar to tumor-bearing mice, CP-treated inflamed mice displayed elevated levels of MDSCs with enhanced production of NO, reactive oxygen species, and a suppressed in vivo natural killer (NK) cell cytotoxic activity indicating CP effects on the host immune system independent of the tumor. We suggest that melanoma therapy with low-dose CP could be efficient only when combined with the neutralization of MDSC immunosuppressive function and chronic inflammatory microenvironment.Journal of Investigative Dermatology advance online publication, 6 December 2012; doi:10.1038/jid.2012.444.
    Full-text · Article · Dec 2012 · Journal of Investigative Dermatology
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