Gemcitabine-treated pancreatic cancer cell medium induces the specific CTL antitumor activity by stimulating the maturation of dendritic cells

Pei, Qingshan; Pan, Jianmei; Zhu, Hao; Ding, Xiwei; Liu, Wenjia; Lv, Ying; Zou, Xiaoping; Luo, Hesheng

doi:10.1016/j.intimp.2013.12.022

Cited by 25 publications

(20 citation statements)

References 32 publications

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“…[69] Several studies have shown that DC vaccine and chemotherapeutic agents have a synergistic effect on PC, inducing tumor antigen-specific CTL. In cell and animal studies, gemcitabine-treated PC cell medium stimulated maturation of DCs inducing antitumor activity of CTL, [11] and concomitant gemcitabine and DC vaccine therapy increased the survival and facilitated recruitment of CD8 + T cells and CTL-mediated tumor cell lysis in a murine PC model. [70,71] In human studies, DCs were recovered and increased after cisplatin and gemcitabine chemotherapy, [29] and DC vaccine combined with chemotherapy was possibly regarded as safe and synergistically effective for inducing tumor antigen-specific CTLs.…”

Section: Innate Immune Cells In Pcmentioning

confidence: 99%

“…[10] Gemcitabine-containing PC cell medium reportedly stimulated DC maturation, and induced T cell proliferation resulting in CTL antitumor immune response. [11] Gemcitabine can directly suppress MDSCs in mice bearing mammary carcinoma, leading to increases in T cells and IFN-γ secretion. [150] Gemcitabine-based chemotherapy reduces the proportion and number of circulating Tregs in patients with PC.…”

Section: Effect Of Chemotherapy On Immune Cellsmentioning

confidence: 99%

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Role of immune cells in pancreatic cancer from bench to clinical application

2016

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Background:Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells.Methods:We searched PubMed for all relevant English language articles published up to March 2016. They included clinical trials, experimental studies, observational studies, and reviews. Trials enrolled at Clinical trial.gov were also searched.Results:PC induces an immunosuppressive microenvironment, and intratumoral activation of immunity in PC is attenuated by inhibitory signals that limit immune effector function. Multiple types of immune responses can promote an immunosuppressive microenvironment; key regulators of the host tumor immune response are dendritic cells, natural killer cells, macrophages, myeloid derived suppressor cells, and T cells. The function of these immune cells in PC is also influenced by chemotherapeutic agents and the components in tumor microenvironment such as pancreatic stellate cells. Immunotherapy of PC employs monoclonal antibodies/effector cells generated in vitro or vaccination to stimulate antitumor response. Immune therapy in PC has failed to improve overall survival; however, combination therapies comprising immune checkpoint inhibitors and vaccines have been attempted to increase the response.Conclusion:A number of studies have begun to elucidate the roles of immune cell subtypes and their capacity to function or dysfunction in the tumor microenvironment of PC. It will not be long before immune therapy for PC becomes a clinical reality.

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Section: Innate Immune Cells In Pcmentioning

confidence: 99%

Section: Effect Of Chemotherapy On Immune Cellsmentioning

confidence: 99%

Role of immune cells in pancreatic cancer from bench to clinical application

2016

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“…Another significant finding in the current study was that co-stimulation of immature DCs with the VNTR 1 antigen and TNF-α was able to robustly induce DC maturation, thereby strongly activating the proliferation of allogeneic T-cells due to the high antigen-presenting ability of mature DCs (25). It has previously been reported that DCs, known as a potent type of antigen-presenting cell, are distributed widely throughout the human body.…”

Section: Discussionmentioning

confidence: 68%

Optimized construction of MUC1-VNTRn DNA vaccine and its anti-pancreatic cancer efficacy

et al. 2017

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Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox® was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells. Additional in vivo experiments in mice were performed to confirm the antitumor effect of the DNA vaccine candidate. The present study successfully constructed the pVAX1-MUC1-VNTRn plasmid, which expresses the target protein in eukaryotic cells. Additionally, upon uptake of the pVAX1-MUC1-VNTRn plasmid, the immature DCs differentiated into mature DCs. The levels of the DC surface molecules cluster of differentiation (CD) 80, CD86, human leukocyte antigen-antigen D related, interleukin (IL)-12, IL-17 and IFN-γ were significantly higher, while the levels of IL-10 and IL-14 were lower, in mature DCs of the stimulated groups compared with the immature DCs of the non-stimulated groups (all P<0.01). In addition, the MUC1-VNTR6 and MUC1-VNTR9 groups, in which DCs were capable of activating autologous T-cells, showed increased IFN-γ-producing T-cells compared with the other groups (strong MUC1-VNTR1, weak VNTR1, VNTR3, VNTR4 and MUC1-cDNA groups; all P<0.001). In addition, the Lethal effect of CTLs on Capan2 cells in these two groups was stronger compared with the other groups (all P<0.001). Furthermore, the induced protective and therapeutic immune responses in mouse experiments showed that the pVAX1-MUC1-VNTR6DNA vaccine likely possessed the strongest immunogenicity, and its ability to inhibit panc02-MUC1 tumor growth was superior to other DNA vaccines (P<0.01). The present study provides compelling evidence that pVAX1-MUC1-VNTRn has the potential to express the target protein in eukaryotic cells, and thatpVAX1-MUC1-VNTR6 was characterized by the strongest Lethal effect in both in vivo and in vitro experiments.

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“…Promising results have recently been demonstrated for various advanced cancers, including melanoma, metastatic non-small-cell lung cancer, renal cell cancer and ovarian cancer (10) using a number of strategies including monoclonal antibodies, checkpoint inhibitors, vaccination and genetically modified immune cells (11–13). Cytotoxic T lymphocytes (CTL) play a pivotal role in cellular immunity and, by recognizing tumor-associated antigen (TAA)-derived short peptide epitopes presented by MHC-class I molecules, they can mediate target cell killing and induce protective anti-tumor immune responses(14).…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

Yuan

Xue

Behboudi

et al. 2017

Clinical Cancer Research

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Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691–699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8+ T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2+ patients with PC and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and CSFE cytotoxicity assays using pancreatic cancer cell lines as targets. Cytokine secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18PC patients, with two CTL lines able to recognise and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T cell responses, including IFN-γ secretion and proliferation, were enhanced and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T cell repertoire of PC patients and that their function can be enhanced by PD-L1 blockade.

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Gemcitabine-treated pancreatic cancer cell medium induces the specific CTL antitumor activity by stimulating the maturation of dendritic cells

Cited by 25 publications

References 32 publications

Role of immune cells in pancreatic cancer from bench to clinical application

Role of immune cells in pancreatic cancer from bench to clinical application

Optimized construction of MUC1-VNTRn DNA vaccine and its anti-pancreatic cancer efficacy

Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA-Specific T Cells in Pancreatic Cancer Patients

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