Efficient delivery of tumor-associated antigens to professional antigen-presenting cells is important for inducing a response in patients receiving cancer immunotherapy. Interferon-gamma (IFN-γ) is used by the immune system to combat viral and fungal infections by restricting cell proliferation and, in some cases, inducing apoptosis. Using IFN-γ to activate target tumor cells prior to antigen loading of dendritic cells (DCs) may enhance the beneficial qualities of whole-cell tumor vaccines. The incubation of melanoma cell cultures with IFN-γ resulted in an increase in the expression of major histocompatibility complex molecules and ICAM-1 but generally decreased the expression of melanoma-associated tumor antigens. Additionally, important immune-stimulating molecules (heat-shock proteins, high-mobility group box-1 protein, and calreticulin) were also present but differentially regulated by IFN-γ. Loading of DCs with IFN-γ-treated tumor cells resulted in a small but significant increase in the expression of CD83-positive DCs, indicating the initiation of DC maturation (p=0.019). IFN-γ treatment of melanoma cell lines prior to antigen loading of DCs may aid in antigen processing and presentation.
Background: Despite advances in surgery and multimodal treatment regimens, Glioblastoma (GBM) continues to have poor overall survival outcomes and associated treatment morbidity. Cell-based immunotherapy is being explored as an option in the treatment of GBM. Treatment of GBM with lymphokine activated killer cells (LAK) generated by interleukin-2 (IL-2) stimulation has been associated with encouraging overall survival rates (Dillman RO et al. J Immunotherapy 2009 32:914-919). Since it has been reported that IL-2-activated lymphocytes can produce cytokines that may influence the differentiation and activation of monocytes (Kirsch M et al. J Neurooncol 1994 20:35-45), we explored the generation of activated monocytes and/or dendritic cells (DC) in LAK cell therapy products. Methods: Magnetic cell isolation of major histocompatibility complex II positive cells (HLA-DR) from LAK cell preparations revealed a small subpopulation of cells expressing CD80 and CD86 which also retained some CD14 expression. We then explored the possibility of generating activated monocytes and/or DC by incubating elutriated monocytes in the conditioned media of LAK cell preparations (LAK-CM) and examining their characteristics in comparison to standard GM-CSF/IL-4 DC or LAK cells. Results: The resulting LAK-CM incubated monocytes showed high levels of expression of CD80 (65.3%), CD86 (72.3%), HLA-DR (83.6%), comparable to the standard GM-CSF/IL-4 DC. The LAK-CM treated monocytes also retained their CD14 expression at (58.2% vs. 58.4%) and had similar levels of phagocytic ability compared to DC (14.7% vs. 12.7%) and demonstrated higher cytotoxicity levels against a model GBM cell line, U251, compared to either LAK cells themselves or the standard GM-CSF/IL-4 generated DC (85.6% vs. 55.9% vs. 60.9%, respectively). Conclusions: Combining lymphocytes and monocytes from elutriated lymphocyte fractions under LAK cell generation conditions (1000 IU/mL IL-2 in AIMV) also yielded similar dendritic cell/activated monocyte phenotypes suggesting that new combinations of cell therapy could be produced using this method with higher tumor cytotoxicity potentials as well as antigen cross presentation capabilities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 768. doi:10.1158/1538-7445.AM2011-768
Amounting evidence indicate that the tissue microenvironment in a developing tumor is created by the tumor to orchestrates molecular and cellular interactions. As a major pathway involved in tumorigenesis, Hedgehog (Hh) signaling is known to regulate tumor microenvironment, but the underlying molecular mechanisms in hedgehog-driven tumors remain unclear. Here we show that smoothened (SMO)-mediated tumor development is accompanied by TGFβ activation in a variety of cell types of the tumor microenvironment, such as keratinocytes, fibroblasts and myeloid-derived suppressor cells. To determine the role of TGFβ signaling for SMO-mediated tumor development, we generated cell type specific TGFβR2flp/flp mice in which SmoM2 expression is accompanied by TGFβR2 knocking out. We found that while K14cre-mediated TGFβRII knockout promoted tumor development, Mx-1cre-mediated TGFβRII knockout suppressed tumor development, indicating a tumor promoting effect of stromal TGFβ signaling. Using EGFP expressing mice for bone marrow transplantation, we determined that most stromal cells with TGFβ signaling activation are derived from bone marrow. To further determine the role of stromal TGFβ signaling for hedgehog signaling-mediated tumor development, we performed bone marrow transplantation experiments in mice that can be induced to develop basal cell carcinomas (BCC). We found that bone marrow cells with TGFβR2 knockout, but not the wild type cells, inhibited tumor development and reduced the size of developed tumors. Reduction of tumor development was associated with decreased expression of multiple inflammation stimulatory cytokines as well as the number of myeloid-derived suppressor cells (MDSCs). The tumor promoting effect of TGFβ signaling is not limited to BCC because tumor growth of B16-F10 cells was also affected by TGFβRII elimination in bone marrow-derived cells. Our data indicate that TGFβ signaling in the tumor microenvironment, not in the keratinocytes, is critical for maintaining the tumor microenvironment to foster tumor development and growth. Citation Format: Jingwu Xie, Eric Qipeng Fan, Dongsheng Gu, Hailan Liu, Xiaoli Zhang, Mark Kaplan, Merv Yoder. A critical role of bone marrow-derived cells for hedgehog-mediated carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2013-2860
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