Enhanced antitumor effects of a dendritic cell vaccine transfected with gastric cancer cell total RNA carrying the 4-1BBL gene in vitro

Abstract

Abstract. T cell-mediated antitumor immunity is a cellular immune response that requires two signals. The dendritic cell (DC) has been considered as the most efficient antigen-presenting cell (APC). It plays essential roles in the induction, regulation and maintenance of antitumor immunity in humans. The 4-1BB/4-1BB ligand (4-1BBL) pathway plays crucial roles in immune response, tumor immunity and autoimmune diseases through transduction of T cell co-stimulatory signals. The aim of this study was to generate the preparation protocol for a DC vaccine transfected with gastric cancer cell total ribonucleic acid (RNA) carrying the 4-1 BBL gene in vitro and to investigate its antitumor effects in murine forestomach carcinoma (MFC). The vaccine was prepared by transfecting MFC total RNAs carrying the 4-1BBL gene into the DCs that were isolated from 615 mouse bones. The T cell proliferation rate in the MFC/4-1BBL/DC group was higher than that in the DC group. The tumor cell kill rate in the MFC/4-1BBL/DC group was higher than that in the DC group. ELISA analysis showed that IL-12 and IFN-γ in the MFC/4-1BBL/DC group were more highly expressed compared to the other group. Collectively, our data demonstrate that the DC vaccine transfected with gastric cancer cell total RNA carrying the 4-1BBL gene has a stronger ability to kill gastric cancer cells through promoting T cell proliferation and enhancing the ability of cytotoxic T lymphocytes (CTLs) to kill gastric carcinoma cells and to secrete IL-12 and IFN-γ. Our results provide an effective therapeutic strategy for treating gastric cancer using a DC vaccine.

Differential Response of Myeloid-Derived Suppressor Cells to the Nonsteroidal Anti-Inflammatory Agent Indomethacin in Tumor-Associated and Tumor-Free Microenvironments

“…In this regard, conversion of MDSCs toward a proinflammatory phenotype by IND treatment may boost DC vaccination protocols and cooperate with other immunotherapeutic regimens (1). Furthermore, IND treatment of tumor-bearing hosts may limit MDSC function and stimulate tumor immunity in an Ag-independent manner which avoids studies of the patient´s HLA phenotype, a problem that is frequently faced in DC or peptide vaccination protocols (38). Interestingly, in an experimental model of mouse breast cancer metastasis, IND was able to restore the anti-metastatic effect of adoptively transferred macrophages, thus supporting the effects of this drug on other tumor-associated myeloid cell populations (39).…”

Antitumor Activity of Lentivirus-mediated Interleukin -12 Gene Modified Dendritic Cells in Human Lung Cancer in Vitro

“…DCs based anti tumor immunotherapy have strong ability to stimulate naïve T lymphocytes and induce effective anti-tumor responses (Guermonprez et al, 2002). There were many reports on DC vaccine in the treatment of melanoma, ovarian, colon, breast and gastric cancer (Song et al, 2012). Another study showed that dendritic cells pulsed with lung cancer cell lysate could induce tumor specific immune response and showed promising clinical outcomes in patient with lung cancer (Han et al, 2006).…”

“…They play a vital role in the initiation of immune response by presenting exogenous and endogenous antigens to T-cells via major histocompatibility complex molecules (Ragde et al, 2004). Following induction of the T-cell response, the activated T cells can differentiate into cytotoxic T lymphocytes (Song et al, 2012). CTL are the major killers of tumor cells, they achieve the killing with the help of CD4+ T cells, which cans induce potential long-termCD8+ T-cell responses by producing various cytokines.…”

“…DCs network system became an attractive approach for research in cancer therapy (Janeway and Medzhitov, 2002). DCs loaded with acid-eluted tumor lysate (Cranmer et al, 2004;Garg et al, 2013) or RNA (Song et al, 2012) are also effective in inducing immunity against tumors for which tumor specific peptides have yet to be identified. Studies have demonstrated that DCs pulsed with tumor associated antigen produce significant therapeutic immunity to tumors with low toxicity (Kaech and Ahmed.2003).…”

Effector function of CTLs is increased by irradiated colorectal tumor cells that modulate OX-40L and 4-1BBL and is reversed following dual blockade

“…In tumor bearing mice, intratumoral OX-40 activation increases CD40 expression on T cells and increases the effector memory T cells (T EM ) subset [ 34 ]. 4-1BBL (TNFRSF9/CD137) costimulation of tumor-specific T cells is important for T-cell activation and 4-1BBL transfected DCs elicit more effective responses and enhanced CTL killing of tumor cells, due to increased expression of perforin and IFN-γ [ 35 ]. In recognition of the importance of these pathways to generating effective antitumor immunity, clinical studies have started to evaluate the effectiveness of humanized agonist antibodies to both OX-40 and 4-1BB [ 36 – 39 ].…”