Antitumor activity of three mouse mammary cancer cell lines after interferon-gamma gene transfection*

Matory, Yvedt L.; Chen, Man; Dorfman, David M.; Williams, Amanda; Goedegebuure, Peter S.; Eberlein, Timothy J.

doi:10.1016/s0039-6060(05)80331-9

Cited by 14 publications

(7 citation statements)

References 14 publications

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“…Thus, local IFNγ secretion at the tumor microenvironment represents a potentially effective strategy to modulate endogenous immunity [11]. IFNγ upregulates major histocompatibility complex class I (MHCI), which correlates with tumor inhibition, and major histocompatibility complex class II (MHCII) antigens on target cells, permitting enhanced antigen presentation [11-13]. Intratumoral administration of IFNγ has been shown to remodel the tumor environment, leading to reduced angiogenesis and normalization of the tumor vasculature [14-15].…”

Section: Introductionmentioning

confidence: 99%

CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

Phan-Lai

Kievit²,

Florczyk

et al. 2014

ACAMC

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Effective elicitation of endogenous immunity is associated with improved prognosis for cancer patients. Clinical evidence in hematological and solid cancers show that intratumoral injection of immunostimulatory genes primes and augments endogenous T cell responses. The ability of pro-inflammatory chemokines/cytokines to facilitate migration/activation of antigen-presenting cells (APC) and lymphocytes prompted our modeling of intratumoral delivery of a chemokine/cytokine combination for breast cancer treatment. Here, we demonstrate that expression of chemokine ligand 21 (CCL21) and interferon gamma (IFNγ) in tumors improves tumor specific T cell recruitment to tumor and activation in the tumor milieu. IFNγ and CCL21 were delivered into tumor cells via plasmids, and transfected cells were seeded to form spheroids on three-dimensional (3D) chitosan-alginate (CA) scaffolds. Co-expression of CCL21 and IFNγ, as evidenced by qRT-PCR and ELISA, induced increased recruitment, binding, and infiltration of anti-neu (p98) peptide specific T cells into the breast tumors as determined by SEM and immunofluorescence assays. The co-expression promoted recruitment of only p98 T cells, but not naïve T cells, demonstrating an antigen-restricted activation. Furthermore, the co-expression impacted T helper (Th) cell immunity, promoting an increase in secretion of pro-inflammatory Th-associated cytokine, tumor necrosis factor alpha (TNFα), and cytotoxic T lymphocyte (CTL)-associated protease, Granzyme B (GzB). Therefore, 3D CA scaffolds may be a useful breast cancer tumor microenvironment model to evaluate T cell function. Further characterization of CCL21-IFNγ mediated anti-tumor immunity will potentially benefit the development of chemokine/cytokine combination platforms as anti-cancer agents.

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Section: Introductionmentioning

confidence: 99%

CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

Phan-Lai

Kievit²,

Florczyk

et al. 2014

ACAMC

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“…Gene transfection of TNF-· into tumor cells has been shown to be more effective than other cytokines in the proposed tumor model [11,12,36]. The antitumor activity of TNF-· was reported when hemorrhagic necrosis of tumor grafts in mice treated with TNF was observed.…”

Section: Discussionmentioning

confidence: 99%

“…10 6 [12]. The same number of transfected cells were injected subcutaneously and compared to nontransfected controls EMT6 and to Lac-z transfected controls.…”

Section: Cell Lines and Tumor Injectionmentioning

confidence: 99%

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Treatment of Established Tumor Is Associated with ICAM-1 Upregulation and Reversed by CD8 Depletion in a Tumor Necrosis Factor-Alpha Gene Transfected Mouse Mammary Tumor

Matory

Dorfman²,

Wu³

et al. 1999

Pathobiology

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Introduction: We have performed TNF-α gene transfection in a mouse mammary cancer line and found significant antitumor effects. We hypothesize that the antitumor effects observed in this model are mediated by ICAM-1 and by the recruitment of CD4+ and CD8+ T cells. In vivo (Balb/c mice) tumor growth inhibition, treatment of established tumor and the effects of ICAM-1 and CD4+ and CD8+ T cells were evaluated. Methods and Results: Gene transfection with highly efficient vectors resulted in secretion of large amounts of TNF-α (ELISA). In vivo antitumor effects were tested. The number of cells required to generate palpable tumor 7–10 days after subcutaneous injection was determined (1 × 10⁶). The same number of transfected cells were injected subcutaneously and compared to nontransfected controls. Tumors were measured blindly and size was analyzed on day 30 by the Wilcoxon rank sum test. Mean tumor size after injection of transfected cells is compared to that of controls. Control tumors reached the maximum allowable size by day 30 (4 cm²). On day 30 EMT6-TNF-α tumors were 0.48 cm² (p < 0.05). The effect of repeat injection (challenge was also tested. Animals were injected with transfected cells or wild-type control on day –6 and challenged with the same number of wild-type tumor cells on day 0. Significant immune protection against subsequent challenge was seen after first time injection with EMT6-TNF-α but not after first time EMT6 wild-type injection (1.62 vs. 4 cm²). Treatment of 6-day-old tumor was also evaluated. On day 30, mean tumor size in animals treated with EMT6-TNF-α was 0.9 cm² compared to 4 cm² for controls. In all experiments, CD8+ T cell depletion and CD4+ T cell depletion caused a reversal of TNF-α-induced inhibitory effects. In addition, in vivo antibody blocking of ICAM-1 in tumor growth experiments reversed antitumor effects (control 4 cm², TNF-α 0.2 cm² and ICAM-1 blocking 3.14 cm²). Using flow cytometry, MHC class I and II and ICAM-1 adhesion molecule expression of transfected tumor was tested. ICAM-I expression was significantly upregulated. MHC class II antigen expression was also increased. TNF-α-transfected human breast cancer was also evaluated. Three cell lines and fresh tumor were transfected to express TNF-α. In vitro analysis revealed ICAM-1 upregulation following transfection. Histologic analysis and immunohistochemical staining revealed TNF-α and ICAM-1 in transfected tumors and not in wild-type tumors. Conclusion: Highly significant in vivo tumor growth inhibition and immune protection after injection with TNF-α-transfected tumors appears to be mediated predominantly by CD8+ T cells and ICAM-1 upregulation. These findings suggest that TNF-α increases recruitment and adhesion of effector T cells.

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“…If further studies confirm upregulation of class I antigen expression following IL2 or IL4 gene transfection, this would be a new finding. There have been previous reports of increased expression of MHC class I antigens in association with interferon-Á [22][23][24][25][26][27][28][29][30][31][32][33]. Fulton [38] has described down regulation of MHC class I following gene transfection of IL10 into 410.4 cells.…”

Section: Discussionmentioning

confidence: 99%

T Cells Mediate Treatment of Six-Day-Old Cytokine-Gene-Transfected Mouse Mammary Tumor

et al. 1999

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We have previously shown that immunologically different mouse mammary cancer cell lines induce antitumor responses after IL2 or IL4 gene transfection. We now report the ability of cytokine-transfected tumors to induce eradication of established wild-type tumor. Animals with 6-day-old tumor treated with IL2-transfected cells also had significantly smaller tumors 2.8 and 1.7 cm² (EMT6 and 410.4). Findings were similar for IL4-transfected cells. Tumor infiltrating lymphocytes or cells from draining lymph nodes demonstrated tumor-specific in vitro cytotoxicity. Immunohistochemical studies revealed T cell infiltrates in transfected tumors.

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Antitumor activity of three mouse mammary cancer cell lines after interferon-gamma gene transfection*

Cited by 14 publications

References 14 publications

CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

Treatment of Established Tumor Is Associated with ICAM-1 Upregulation and Reversed by CD8 Depletion in a Tumor Necrosis Factor-Alpha Gene Transfected Mouse Mammary Tumor

T Cells Mediate Treatment of Six-Day-Old Cytokine-Gene-Transfected Mouse Mammary Tumor

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Antitumor activity of three mouse mammary cancer cell lines after interferon-gamma gene transfection*

Cited by 14 publications

References 14 publications

CCL21 and IFN&#947; Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

CCL21 and IFN&#947; Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

Treatment of Established Tumor Is Associated with ICAM-1 Upregulation and Reversed by CD8 Depletion in a Tumor Necrosis Factor-Alpha Gene Transfected Mouse Mammary Tumor

T Cells Mediate Treatment of Six-Day-Old Cytokine-Gene-Transfected Mouse Mammary Tumor

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CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer

CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer