Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model.
OBJECTIVE
Melanoma is a common and deadly tumor that upon metastasis to the central nervous system has a median survival duration of <6 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. We hypothesized that WP1193, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of IFN-alpha against metastatic melanoma.


METHODS
Combinational therapy of STAT3 blockade agents with IFN-alpha was investigated in a metastatic and an established syngeneic intracerebral murine tumor model of melanoma. The immunologic in vivo mechanisms of efficacy were investigated by T-cell and natural killer (NK) cell cytotoxic assays.


RESULTS
IFN-alpha immunotherapy was synergistic with WP1193 showing marked in vivo efficacy against metastatic and established intracerebral melanoma. At autopsy, it was noted that there was a decreased trend in mice with melanoma developing leptomeningeal disease treated with combinational therapy. The combinational approach enhanced both NK-mediated and T-cell-mediated antitumor cytotoxicity.


CONCLUSIONS
The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-alpha immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach.
Kong
Ling-Yuan
LY
Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Gelbard
Alexander
A
Wei
Jun
J
Reina-Ortiz
Chantal
C
Wang
Yongtao
Y
Yang
Eric C
EC
Hailemichael
Yared
Y
Fokt
Izabela
I
Jayakumar
Arumugam
A
Qiao
Wei
W
Fuller
Gregory N
GN
Overwijk
Willem W
WW
Priebe
Waldemar
W
Heimberger
Amy B
AB
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003487:Cyanoacrylates / Q000737:chemistry / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015151:Immunoblotting; D007155:Immunologic Factors / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D003487:Cyanoacrylates; D007155:Immunologic Factors; D016898:Interferon-alpha; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C551527:WP 1193
Cytokine. 2003 Sep 21;23(6):190-9
12967644
J Neurosurg. 1998 Jan;88(1):11-20
9420067
Immunity. 1999 Jan;10(1):39-49
10023769
Nat Rev Immunol. 2007 Jan;7(1):41-51
17186030
EMBO J. 1998 Feb 16;17(4):1006-18
9463379
Cancer Res. 2006 Mar 15;66(6):3188-96
16540670
Cancer Immunol Immunother. 2010 Jan;59(1):13-26
19430787
Clin Exp Metastasis. 1989 Jan-Feb;7(1):15-23
2908827
Nat Rev Cancer. 2004 Feb;4(2):97-105
14964307
Curr Opin Oncol. 1996 Mar;8(2):167-74
8727310
J Immunol. 2002 Sep 1;169(5):2253-63
12193690
Clin Cancer Res. 2008 Sep 15;14(18):5759-68
18794085
Clin Exp Metastasis. 1986 Jul-Sep;4(3):191-203
2427270
Proc Natl Acad Sci U S A. 1985 Jan;82(1):188-92
3918301
J Exp Med. 2005 Sep 5;202(5):637-50
16129706
Cancer. 1991 Jul 1;68(1):88-92
2049759
Cancer Res. 1992 Mar 1;52(5):1123-8
1737371
Nat Med. 2004 Sep;10(9):909-15
15340416
Immunol Today. 1995 Oct;16(10):487-94
7576053
J Exp Med. 2009 Jul 6;206(7):1457-64
19564351
Surg Neurol. 1991 Mar;35(3):244-7
1996455
Blood. 2006 Sep 1;108(5):1571-9
16645171
J Immunother. 2004 May-Jun;27(3):184-90
15076135
Clin Cancer Res. 2007 Mar 1;13(5):1362-6
17332277
Clin Exp Metastasis. 2008;25(7):799-810
18649117
Cancer Cell. 2009 Feb 3;15(2):91-102
19185844
J Immunol. 2001 Mar 1;166(5):2961-9
11207245
Cancer Cell. 2009 Feb 3;15(2):114-23
19185846
Nature. 2001 Sep 13;413(6852):165-71
11557981
J Immunol. 1989 Jun 15;142(12):4241-7
2498428
Clin Cancer Res. 2008 Dec 15;14(24):8314-20
19088050
J Immunol. 2009 Jun 15;182(12):7398-407
19494262
Gene Ther. 1999 Jul;6(7):1258-66
10455434
J Exp Med. 2006 Apr 17;203(4):1021-31
16606674
Cancer Cell. 2009 Feb 3;15(2):103-13
19185845
Cancer Res. 2007 Oct 15;67(20):9630-6
17942891
Cancer Chemother Rep. 1966 Mar;50(3):163-70
5910392
Nat Med. 2005 Dec;11(12):1314-21
16288283
J Neurosci. 1999 Jul 1;19(13):5236-44
10377335
Clin Cancer Res. 2004 Mar 1;10(5):1670-7
15014018
Cancer Immunol Immunother. 2009 Jul;58(7):1023-32
19002459
J Neurooncol. 1985;3(1):61-7
2987429