The toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism

Hua Yang, Craig M. Brackett, Vanessa Morales-Tirado, Zezhong Li, Qing Zhang, Matthew Wilson, Camille Benjamin, Wayne Harris, Edmund K. Waller, Andrei V. Gudkov, Lyudmila G. Burdelya, Hans E. Grossniklaus

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19 Citations (Scopus)

Abstract

Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ~50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-κB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5-positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug.

Original languageEnglish (US)
Pages (from-to)2936-2950
Number of pages15
JournalOncotarget
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2016

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Toll-Like Receptor 5
Natural Killer Cells
Melanoma
Neoplasm Metastasis
Liver
Eye Neoplasms
Intraocular Injections
CBLB502
Subcutaneous Injections
Life Expectancy
Names
Liver Diseases
Hepatocytes

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

The toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. / Yang, Hua; Brackett, Craig M.; Morales-Tirado, Vanessa; Li, Zezhong; Zhang, Qing; Wilson, Matthew; Benjamin, Camille; Harris, Wayne; Waller, Edmund K.; Gudkov, Andrei V.; Burdelya, Lyudmila G.; Grossniklaus, Hans E.

In: Oncotarget, Vol. 7, No. 3, 01.01.2016, p. 2936-2950.

Research output: Contribution to journalArticle

Yang, H, Brackett, CM, Morales-Tirado, V, Li, Z, Zhang, Q, Wilson, M, Benjamin, C, Harris, W, Waller, EK, Gudkov, AV, Burdelya, LG & Grossniklaus, HE 2016, 'The toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism', Oncotarget, vol. 7, no. 3, pp. 2936-2950. https://doi.org/10.18632/oncotarget.6500
Yang, Hua ; Brackett, Craig M. ; Morales-Tirado, Vanessa ; Li, Zezhong ; Zhang, Qing ; Wilson, Matthew ; Benjamin, Camille ; Harris, Wayne ; Waller, Edmund K. ; Gudkov, Andrei V. ; Burdelya, Lyudmila G. ; Grossniklaus, Hans E. / The toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. In: Oncotarget. 2016 ; Vol. 7, No. 3. pp. 2936-2950.
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