Adjuvants and myeloid-derived suppressor cells: Enemies or allies in therapeutic cancer vaccination

Fernández, Audry; Oliver, Liliana; Alvarez, Rydell; Fernández, Luis E.; Lee, Kelvin P.; Mesa, Circe

doi:10.4161/hv.29847

Cited by 38 publications

(31 citation statements)

References 113 publications

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“…Although the response of MDSCs to NLRP3 and TLR9 stimulation is complex [58], the decrease in cytokine responses observed here is consistent with enhanced MDSC activity. Interestingly, the distribution of CpG within lesion macrophages was comparable for both the free CpG and NP-CpG treatment groups; therefore, the therapeutic differences found do not appear to involve direct targeting and modulation of the primary host cell of the parasite.…”

Section: Discussionsupporting

confidence: 83%

“…Notably, in the NP-CpG group, the distribution within the CD11b + population (macrophages and granulocytes) was associated with an increased proportion of Ly6G + cells, which includes neutrophils/granulocytes and granulocytic MDSCs [46]. The increase in MDSC-like cells is consistent with studies indicating that activation via CpG [56] and/or through NLRP3 [57] can drive the expansion of MDSCs [58–60] via the induction of IL-1β. Interestingly, IL-1β has been shown to have variable roles in leishmaniasis, dependent upon the infective species [61–63]; notably, IL-1β was found to ameliorate L. (V.) braziliensis infection [63] but have an opposing effect for L. major , where MDSCs have been shown to exacerbate disease [62].…”

Section: Discussionsupporting

confidence: 70%

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Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

et al. 2016

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Leishmania (Viannia) panamensis (L. (V.) panamensis) is a species of protozoan parasites that causes New World leishmaniasis, which is characterized by a hyper-inflammatory response. Current treatment strategies, mainly chemotherapeutic, are suboptimal due to adverse effects, long treatment regimens, and increasing drug resistance. Recently, immunotherapeutic approaches have shown promise in preclinical studies of leishmaniasis. As NPs may enable broad cellular immunomodulation through internalization in phagocytic and antigen-presenting cells, we tested the therapeutic efficacy of biodegradable NPs encapsulating a pathogen-associated molecular pattern (PAMP), CpG-rich oligonucleotide (CpG; NP-CpG), in mice infected with L. (V.) panamensis. NP-CpG treatment reduced lesion size and parasite burden, while neither free CpG nor empty NP showed therapeutic effects. NP-encapsulation led to CpG persistence at the site of infection along with an unexpected preferential cellular uptake by myeloid derived suppressor cells (MDSCs; CD11b+Ly6G+Ly6C−) as well as CD19+ dendritic cells. This corresponded with the suppression of the ongoing immune response measured by the reduction of pathogenic cytokines IL-10 and IL-13, as well as IL-17 and IFNγ, in comparison to other treatment groups. As chronic inflammation is generally associated with the accumulation of MDSCs, this study may enable the rational design of cost-effective, safe, and scalable delivery systems for the treatment of inflammation-mediated diseases.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 70%

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

et al. 2016

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“…(36) Likewise, co-administration of toll-like receptor (TLR) ligands along with GM-CSF expressing vaccines may reverse MDSC induction and further promote anti-tumor immunity, driving stronger responses . (37) In some clinical studies, however, GVAX immunotherapy has lead to a reduction in circulating MDSCs. (38) The relationship between GM-CSF expression and immunoregulatory mechanisms requires further study.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma

Curry

Gorrepati

Piesche

et al. 2016

Clinical Cancer Research

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Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma. Experimental Design: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 106 GM-K562 cells or 1 × 107 GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation. Results: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4+ cells and PD-1 and 4-1BB by CD8+ cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4+ T lymphocytes. Conclusions: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885–96. ©2016 AACR.

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“…Adjuvants to augment cancer immunotherapy and overcome MDSC mediated immunosuppression provide immunostimulatory signals boosting the immune response via bacterial products or Toll-like receptors, cytokines and growth factors or by immunostimulatory delivery systems (e.g., nanoparticles targeting TAMs to deliver tumor antigens) [177,178]. Toll-like receptor-9 (TLR9) agonist CpG oligonucleotids (ODNs) affected on TLR9 expressing M-MDSC cells.…”

Section: Therapeutic Interventions Targeting Tams and Mdscs Tuninmentioning

confidence: 99%

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

Szebeni¹,

Vízler

Nagy³

et al. 2016

IJMS

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Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review some of these indisputable experimental and clinical evidences of cancer related smouldering inflammation. The most common myeloid infiltrate in solid tumors is composed of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells promote tumor growth by several mechanisms, including their inherent immunosuppressive activity, promotion of neoangiogenesis, mediation of epithelial-mesenchymal transition and alteration of cellular metabolism. The pro-tumoral functions of TAMs and MDSCs are further enhanced by their cross-talk offering a myriad of potential anti-cancer therapeutic targets. We highlight these main pro-tumoral mechanisms of myeloid cells and give a general overview of their phenotypical and functional diversity, offering examples of possible therapeutic targets. Pharmacological targeting of inflammatory cells and molecular mediators may result in therapies improving patient condition and prognosis. Here, we review experimental and clinical findings on cancer-related inflammation with a major focus on creating an inventory of current small molecule-based therapeutic interventions targeting cancer-related inflammatory cells: TAMs and MDSCs.

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Adjuvants and myeloid-derived suppressor cells: Enemies or allies in therapeutic cancer vaccination

Cited by 38 publications

References 113 publications

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma

Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

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