PGE 2 is a well-known immunomodulator produced in the immune response by APCs, such as dendritic cells (DCs), the most potent APC of the immune system. We investigated the PGE 2 biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE 2 and other proinflammatory mediators, such as leukotriene B 4 and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE 2 compared with the LPS-induced COX-2-produced PGE 2 . Treatment of BM-DC with exogenous PGE 2 induced the production of large amounts of IL-10 and less IL-12p70. In addition, selective inhibition of COX-2, but not COX-1, was followed by significant decrements in PGE 2 and IL-10, a concomitant restoration of IL-12 production, and an enhancement of DC stimulatory potential. In contrast, we found no demonstrable role for leukotriene B 4 or NO. In view of the potential of PGE 2 to stimulate IL-10, we examined the possibility that the suppressive effect of PGE 2 is mediated via IL-10. We found that exogenous IL-10 inhibits IL-12p70 production in the presence of NS-398, a COX-2 selective inhibitor, while the inhibitory effects of PGE 2 were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE 2 up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.

Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions.

Dendritic Cells Issued in Vitro from Bone Marrow Produce PGE2 That Contributes to the Immunomodulation Induced by Antigen-Presenting Cells

As a means of enhancing immunity to gliomas, we investigated local delivery of rat, bone marrow-derived dendritic cells (DCs) into rat 9L gliosarcoma tumors and into 9L tumors induced to undergo apoptosis by gamma knife radiosurgery. Contrary to other tumors, local delivery of DCs had no therapeutic effect on 9L gliomas, even when tumor apoptosis was induced via radiosurgery, which leads to efficient "loading" of the DCs with tumor antigen. To determine whether antigen-presenting cells, such as DCs, were viable in tumors, we carried out multiparametric staining of 9L tumors, using phycoerythrin-conjugated OX6 (MHC class II) or OX62 (DC specific) and FITC-labeled Val-Ala-Asp-fluoromethyl ketone (FITC-VAD-FMK; activated caspases). It was determined that DCs were undergoing apoptosis in these tumors. We therefore sought to determine which glioma cell surface receptors or components of the extracellular matrix in gliomas influenced DC viability. Hyaluronan (HA) is a major component of glioma extracellular matrix and has been found to support tumor cell migration and metastasis. However, its influence on the immune system, and particularly on DCs, via its receptor CD44 is not well documented. Using reverse transcription-PCR, Northern blot, and Western blot analyses, we determined that HA stimulated production of inducible nitric oxide synthase (iNOS) in DCs. NO production by HA-stimulated DCs was then verified biochemically. NO production was dependent on the size of HA; intermediate HA fragments had the greatest capacity to induce NO production in DC, whereas completely digested HA oligosaccharides failed to induce NO. Furthermore, N-monomethyl-L-arginine, an inhibitor of iNOS, completely blocked HA-induced NO production by DCs. Because induction of NO results in the induction of apoptosis in macrophages as well as other cells, DCs treated with HA were examined for apoptosis in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP biotin nick-end labeling assays. It was demonstrated that HA induced apoptosis in DCs and that induction of apoptosis was dependent on the production of NO because it was entirely inhibited by N-monomethyl-L-arginine. Using flow cytometric analyses with FITC-VAD-FMK, which is specific for activated caspases, we also determined that induction of apoptosis in DCs with HA could be titrated. Coincubation of 9L tumor cells with DCs was found to induce apoptosis in DCs as indicated by fluorescent staining with FITC-VAD-FMK. Specificity of this reaction for CD44-HA interactions was determined by pretreatment of DCs with anti-CD44 or pretreatment of 9L tumor cells with hyaluronidase, which blocked the induction of apoptosis in DCs. These data indicate that HA expressed by gliomas may contribute to their immunosuppressive effects by promoting apoptosis among professional antigen-presenting cells such as DCs via iNOS induction after CD44-HA interactions.

https://cancerres.aacrjournals.org/content/canres/62/9/2583.full.pdf

Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas.

The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

/pdf/the-future-of-glioblastoma-therapy-synergism-of-standard-of-3r759oj5hr.pdf

The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

RCC accounts for < 3% of adult solid tumours, and each year 30 000 new cases in the USA and 20 000 in the European Union are detected. Men are affected twice as often as women, with the highest incidence in those aged 50±70 years. Despite modern imaging methods and early diagnosis, a third of patients present with metastatic disease and up to half with localized disease progression after radical nephrectomy. The incidence of RCC has increased by >30% in the last decade, as a result of better imaging, early diagnosis and environmental factors. Except for hereditary forms, several risk factors have been identi®ed, e.g. smoking, obesity, hyper tension, occupational petrol and heavy-metal exposure, diuretics, haemodialysis, and pre-existing kidney diseases, including stones and infections [1].

Recent advances in kidney cancer and metastatic disease

Presentation of cell-associated antigen to T cells is a critical event in the initiation of an anti-tumor immune response but it appears to often be deficient or limiting. Here we report an experimental system for stimulation of human T lymphocytes using autologous antigen presenting cells (APCs) and autologous tumor cells. Two types of APCs were prepared from human bone marrow: MC and DC. MC were produced by using GM-CSF and SCF. DC were obtained with the same cytokines plus IL-4. DC and MC were generated in parallel from the same patients and their phenotypes and capacities to prime T lymphocytes were analyzed and compared. MC were CD14+, CD1a-, CD33+ and HLA-DR+. Two populations of DC were defined: immature DC were uniformly CD1a-; mature DC expressed CD1a, CD80, CD86, HLA-DR, CD54 and CD58 but lacked surface CD14. Stimulation of autologous T lymphocytes was studied by measuring their proliferation and cytotoxic function. In more than 80% of our experiments the proliferation of autologous T lymphocytes cocultured with APC pulsed or not with tumor cell lysates was higher than that of T cells cultured alone. DC were more effective than MC in stimulating proliferation of lymphocytes. The capacity of a patient's autologous bone marrow-derived APC to stimulate T cells when exposed to autologous tumor cell lysates suggest that such antigen-exposed APC may be useful in specific anti-tumor immunotherapy protocols.

In vitro immunization of patient T cells with autologous bone marrow antigen presenting cells pulsed with tumor lysates.

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In vitro immunization of patient T cells with autologous bone marrow antigen presenting cells pulsed with tumor lysates.