Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

Guo, Jun; Wang, B; Zhang, M; Chen, T; Yu, Yizhi; Régulier, Etienne; Homann, H. E.; Qin, Zhihai; Ju, Dianwen; Cao, Xuetao

doi:10.1038/sj.gt.3301688

Cited by 54 publications

(41 citation statements)

References 56 publications

(57 reference statements)

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“…Our previous studies have shown that chemokine gene transfer can enhance DC-mediated and T cell-dependent anti-tumor immunity and thus represents a potent anti-tumor immunotherapeutic approach. [35][36][37] Therefore, increased chemokine secretion by DAMP-stimulated DCs is expected to exert strong chemoattractant effects on DCs and T cells, resulting in improved protective immunity and an enhanced T-cell response.…”

Section: Discussionmentioning

confidence: 99%

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

et al. 2013

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The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns (DAMPs) can activate immune cells, including dendritic cells (DCs), via Toll-like receptors (TLRs); however, the role of DAMPs released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer (CRC) cells treated with oxaliplatin (OXA) and/or 5-fluorouracil (5-Fu) released high levels of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known DAMPs. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-1b, TNF-a, MIP-1a, MIP-1b, RANTES and IP-10 production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-c-producing Th1 response both in vitro and in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-c-producing Th1 response in TLR4-deficient DCs. Collectively, these results demonstrate that DAMPs released from chemically stressed cancer cells can activate DCs via TLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by DAMPs.

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Section: Discussionmentioning

confidence: 99%

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

et al. 2013

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“…Specifically related to the current study, various forms of immunotherapy were shown to reduce B16 and 3LL spontaneous metastasis through CTL-and NK-dependent responses (32,33), and experimental metastases of B16, but not 3LL, were reported to be under NK control when tumor cells were administered i.v. at low numbers (34).…”

Section: Sectionmentioning

confidence: 99%

Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor

Glasner

Avraham

Rosenne

et al. 2010

The Journal of Immunology

210

177

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Clinical practice does not consider perioperative paracrine and neuroendocrine stress responses as risk factors for cancer recurrence, although recent animal studies provided supportive evidence. Suggested mechanisms include the effects of stress-hormones on tumor cells and on host physiology. In this study, in mice undergoing primary tumor excision, we tested the survival-enhancing potential of perioperative blockade of catecholamines and prostaglandins, and studied potential mediating mechanisms. C57BL/6J mice were inoculated intrafootpad with syngeneic B16F10.9-melanoma or Lewis lung carcinoma, and the paw was amputated when a developing tumor exceeded 100 μl. The clinically used β-adrenergic antagonist propranolol, and/or the cyclooxygenase-2 inhibitor etodolac, were administered once before amputation, and recurrence-free survival was monitored. In different studies, NK cytotoxicity, leukocytes' molecular functional markers, and vascular endothelial growth factor secretion by tumor cells were studied in the context of surgery and drug treatments. The findings indicated that the combination of propranolol and etodolac, but neither drug alone, significantly and markedly improved survival rates in both tumor models, and was as effective as established immunostimulatory agents (IL-12 and polyinosinic-polycytiylic acid). Surgery markedly reduced NK cytotoxicity and NK cell expression of Fas ligand and CD11a, reduced all circulating lymphocyte-subtype concentrations, and increased corticosterone levels. Propranolol and etodolac administration counteracted these perturbations. B16 and 3LL secreted vascular endothelial growth factor in vitro, but secretion was not affected by catecholamine agonists, prostaglandins, corticosterone, propranolol, or etodolac. Overall, propranolol and etodolac administration, which could be applied perioperatively in most cancer patients with minimal risk and low cost, has counteracted several immunologic and endocrinologic perturbations and improved recurrence-free survival rates in mice undergoing primary tumor excision.

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“…The expression of CLL19 in a breast cancer cell line-mediated rejection of the transduced tumor through a mechanism involving NK and CD4 + T cells. [25][26][27] CX3CL1/Fractalkine is a unique CX3C chemokine acting as an adhesion molecule in its membrane form and behaving as a true chemokine in its soluble form. It serves as a potent chemoattractant for monocytes, NK cells and T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…5 23,24 FK also was shown to have tumor suppressive activity, following FK gene transfer into murine lung, colon carcinoma and lymphoma cell lines. [25][26][27][28] In this study, we used FK eukaryotic expression vector (pIRES-FK) to transfer the mouse FK to the murine HCC cell line MM45T.Li, and then inoculated these cells into mice to test their antitumor activity. The pIRES-FKinduced local recruitment of immune cells and suppressed tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma

Tang

et al. 2007

Gene Ther

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CX3CL1/Fractalkine(FK), a chemokine existing in both secreted and membrane anchored form, was reported to induce suppressive activities in tumor models. Here, we demonstrate for the first time the antitumor effects of FK in murine hepatocellular carcinoma (HCC) by constructing a FK eukaryotic expression vector (pIRES-FK) and transferring it into such tumor cells. Tumor rejection experiments were performed by injecting FK gene-modified murine HCC cell line (MM45T.Li) into immunocompetent mice, which significantly inhibited tumorigenicity or growth of MM45T.Li-FK cells. Immunohistochemistry examination and fluorescenceactivated cell sorting analyses revealed both CD4 + and CD8 + T cells infiltration within the tumor together with a marked increase of these cells in the peripheral blood. Splenic lymphocyte from mice treated with MM45T.Li-FK were effective in the induction of tumor-specific cytotoxic T cells . We also observed an increased production of IL-2 and IFN-g in MM45T.Li-FK tumor tissue. Our results suggest that transfer of the FK gene into tumor cells could elicit a specific antitumor immunity capable of inhibiting tumor growth which lead to increased survival of tumor-bearing hosts. FK should be considered as a chemokine suitable for cancer immunoprevention or gene therapy.

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Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

Cited by 54 publications

References 56 publications

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor

Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma

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