Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma through Nuclear Hormone Receptor Activation

Pencheva, Nora; Buss, Colin G.; Posada, Jessica M.; Merghoub, Taha; Tavazoie, Sohail F.

doi:10.1016/j.cell.2014.01.038

Cited by 154 publications

(158 citation statements)

References 38 publications

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“…cGAMP also increased tumor-infiltrating CD8 T-cell numbers and delayed tumor growth when injected into engrafted melanoma derived from Tyr::N-ras (Q61K) INK4A −/− mice (19) (Fig. S1) and B-raf (V600E/+) PTEN −/− CDKN2A −/− mice (20) (Fig. S1).…”

Section: Intratumoral Injection Of Cgamp Promotes the Induction Of CDmentioning

confidence: 99%

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.

439

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 Injection Of Cgamp Promotes the Induction Of CDmentioning

confidence: 99%

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.

439

425

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“…Activation of LXRs led to increased expression of ABCA1 and IDOL, triggering degradation of the LDL-receptor, consequently decreasing cholesterol levels and thereby reducing growth and survival of the tumour. However, the hitherto strongest indication that LXRs are therapeutic targets for cancers was recently published showing that activation of LXR suppressed melanoma invasion, angiogenesis, tumour progression, and metastasis [9]. LXR activation displayed melanoma-suppressive cooperatively with the frontline regimens dacarbazine, B-Raf inhibition, and CTLA-4 antibody and robustly inhibited melanomas that had acquired resistance to B-Raf inhibition or dacarbazine.…”

Section: Introductionmentioning

confidence: 99%

LXR Inhibits Proliferation of Human Breast Cancer Cells through the PI3K-Akt Pathway

Hassan

Paniccia

Russo

et al. 2015

Nuclear Receptor Research

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Abstract. The oxysterol receptors, LXRs, have recently been shown to reduce cell and tumour growth in various model systems. Activation of LXRs could therefore provide a novel approach for treatment of cancers. Here we show that LXR is the main executor of the antiproliferative effect in human breast cancer cells. LXR inhibits the activation of growth factor-induced triggering of the PI3K-Akt pathway. Phosphorylation of several protein kinases in this pathway, including Akt and the PI3K itself, is reduced upon activation of LXR. Both mRNA and protein expression levels of the PTEN and PHLPPL protein phosphatases were induced by LXR and the amount of the second messenger PIP3 reduced-a pivotal activator signalling molecule in the PI3K. This suggest that the intracellular signalling cascade mediating proliferative cues from growth factors is the responsible mechanisms underlying the antiproliferative effects of LXR in human breast cancer cells. This provides novel and in-depth insights of how LXR works in cancer cells where the LXRs control the activity of intracellular signalling cascades that regulate proliferation.

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“…LXR agonists impair the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts and decrease tumor growth by inhibiting angiogenesis (51). Furthermore, LXRβ agonist treatment induces apolipoprotein E secretion by stromal and tumor cells and blocks tumor growth, angiogenesis and metastasis (52). However, further studies are required in order to investigate whether other types of cell in the tumor microenvironment are influenced by LXRβ agonists.…”

Section: Lxrs and Tumor Immunitymentioning

confidence: 99%

Liver X receptors as potential targets for cancer therapeutics (Review)

Huang

Chen

et al. 2017

Oncol Lett

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Abstract. Liver X receptors (LXRs) are important members of the nuclear receptor family that were originally determined to function in cholesterol transport and the regulation of immune responses. Synthetic LXR ligands have been developed to treat various diseases including diabetes, Alzheimer's disease and atherosclerosis. Previous studies have suggested that LXRs are also involved in numerous types of cancer and are therefore potential targets for cancer therapeutics. The present review summarizes LXR ligands and their mechanisms of action, the effects of LXRs in different types of cancer and their potential applications in clinical treatment. Together, the studies discussed in the present review indicate that LXRs may be potential targets for cancer therapeutics.

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Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma through Nuclear Hormone Receptor Activation

Cited by 154 publications

References 38 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

LXR Inhibits Proliferation of Human Breast Cancer Cells through the PI3K-Akt Pathway

Liver X receptors as potential targets for cancer therapeutics (Review)

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