Difference of interferon-α and interferon-β on melanoma growth and lymph node metastasis in mice

Roh, Mi Ryung; Zheng, Zhenlong; Kim, Hyun Sook; Jeung, Hei Cheul; Rha, Sun Young; Chung, Kee Yang

doi:10.1097/cmr.0b013e32835e7713

Cited by 20 publications

(17 citation statements)

References 53 publications

(42 reference statements)

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“…These tumor extracts were indeed able to block the growth of B16 cells in a type I IFN-dependent manner (Fig. S7), a finding that is consistent with previous reports showing that type I IFNs block proliferation and induce apoptosis of B16 cells (22,23). Together these data indicate that IFN-β is required for the generation of tumor-infiltrating CD8 T cells and for the antitumor activity induced by intratumoral cGAMP.…”

Section: Intratumoral Sting Activation Leads To Systemic Cd8 T-cell-msupporting

confidence: 80%

“…Second, type I IFNs may increase CD8 T-cell infiltration into cGAMP-injected tumors (6) and directly promote their survival and proliferation in the tumor microenvironment (24). However, our data suggest that the potent local antitumor efficacy is not explained by increased CD8 T-cell infiltration of cGAMP-injected tumor but rather by a direct inhibitory effect of type I IFNs on the tumor itself (22,23). Representative plots are given (Upper); each symbol represents an independent mouse (Lower).…”

Section: Discussioncontrasting

confidence: 52%

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STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Demaria

Gassart

Coso

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

459

425

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Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.M etastatic melanoma is a highly aggressive cancer with a fast increasing incidence worldwide. Unless diagnosed early and surgically resected, the disease becomes metastatic and life threatening. Both chemotherapy and irradiation are ineffective. Novel therapies that target oncogenic drivers have brought some improvements, but tumor cells escape regularly (1). Melanoma is a prototypical immunogenic tumor, as shown by the occurrence of spontaneous CD8 T-cell responses that drive tumor regressions and by the identification of CD8 T cells that recognize melanoma antigens (2, 3). Although many immunotherapeutic strategies have been developed to induce such responses, clinical efficacies have been poor. More recently, "checkpoint blockade" therapies that target T-cell-inhibitory pathways mediated by CTLA4 (4) and PD1 (5) have yielded encouraging clinical results and demonstrated that spontaneous CD8 T-cell responses in tumors can be boosted to treat melanoma.The mechanisms that drive spontaneous antitumor immune responses are poorly understood. Type I IFNs (IFN-α and IFN-β) may play a role as the expression type I IFN-related genes in primary melanoma has been associated with spontaneous tumor regressions (6) and correlated to the tumor infiltration by specific CD8+ T cells (6, 7). Furthermore, the lack of type I IFN signaling or IFN-β expression inhibited the generation of tumor-specific CD8 T cells and accelerated tumor growth in a murine melanoma mo...

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Section: Intratumoral Sting Activation Leads To Systemic Cd8 T-cell-msupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 52%

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Demaria

Gassart

Coso

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

459

425

View full text Add to dashboard Cite

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“…Treatment with IFN- α -2b and IFN- β -1a also resulted in decreased proliferation index of human melanoma xenograft tumors as manifest by immunohistochemical staining with Ki-67; again, IFN- β -1a-treated tumors showed less staining with Ki-67 than did IFN- α -2b-treated tumors [37]. In experiments by Garbe et al, IFN- α and IFN- β both showed concentration-dependant inhibition of proliferation of three melanoma cell lines, but IFN- β had the smallest IC 50 for all three cell lines tested.…”

Section: Melanomamentioning

confidence: 99%

“…Kubo et al showed that IFN- β induced apoptosis dose-dependently in 7 melanoma cell lines as well as induced cleavage of caspase 3 in these cell lines [42]. The number of apoptotic cells in human melanoma xenograft tumors was significantly increased in IFN- α -2b- and IFN- β -1a-treated tumors compared with untreated tumors, with IFN- β -1a having a greater apoptotic effect than IFN- α -2b [37]. …”

Section: Melanomamentioning

confidence: 99%

“…Protein levels of VEGF-C and VEGFR-3 in SK-MEL-24 cells decreased in response to in vitro treatment with IFN- α 2b or IFN- β 1a, with IFN- α 2b showing an earlier and more sustained response compared with IFN- β 1a. Moreover, treatment with IFN- α 2b or IFN- β 1a also decreased secretory VEGF-C levels, with a superior effect by IFN- α 2b [37]. In human melanoma IGR 1 cells, treatment with 500 IU/mL of either IFN- α or IFN- β significantly and similarly led to a decrease in VEGF production compared to controls [39].…”

Section: Melanomamentioning

confidence: 99%

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Type I Interferons: Key Players in Normal Skin and Select Cutaneous Malignancies

Ismail

Yusuf

2014

Dermatology Research and Practice

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Interferons (IFNs) are a family of naturally existing glycoproteins known for their antiviral activity and their ability to influence the behavior of normal and transformed cell types. Type I Interferons include IFN-α and IFN-β. Currently, IFN-α has numerous approved antitumor applications, including malignant melanoma, in which IFN-α has been shown to increase relapse free survival. Moreover, IFN-α has been successfully used in the intralesional treatment of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In spite of these promising clinical results; however, there exists a paucity of knowledge on the precise anti-tumor action of IFN-α/β at the cellular and molecular levels in cutaneous malignancies such as SCC, BCC, and melanoma. This review summarizes current knowledge on the extent to which Type I IFN influences proliferation, apoptosis, angiogenesis, and immune function in normal skin, cutaneous SCC, BCC, and melanoma.

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Heterozygous loss of keratinocyte TRIM16 expression increases melanocytic cell lesions and lymph node metastasis

Sutton

Cheung

Massudi

et al. 2019

J Cancer Res Clin Oncol

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Purpose The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. Methods To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. Results Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. Conclusion This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.

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Difference of interferon-α and interferon-β on melanoma growth and lymph node metastasis in mice

Cited by 20 publications

References 53 publications

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Type I Interferons: Key Players in Normal Skin and Select Cutaneous Malignancies

Heterozygous loss of keratinocyte TRIM16 expression increases melanocytic cell lesions and lymph node metastasis

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