PARP Inhibition Activates STAT3 in Both Tumor and Immune Cells Underlying Therapy Resistance and Immunosuppression In Ovarian Cancer.
PARP inhibition
STAT3
immunosuppression
ovarian cancer
therapy resistance
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2021
2021
Historique:
received:
12
06
2021
accepted:
16
11
2021
entrez:
27
12
2021
pubmed:
28
12
2021
medline:
28
12
2021
Statut:
epublish
Résumé
Despite the promising activity of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in many cancer types with defects in the DNA damage response the majority of the treated patients acquire PARPi resistance and succumb to their diseases. Consequently, there is an urgent need to identify the mechanisms of PARPi resistance. Here, we show that PARPi treatment promotes STAT3 activation in ovarian cancer cells, tumor-associated immune cells and fibroblasts, resulting in PARPi resistance and immunosuppression. Comparison of ovarian cancer patient-matched tumor biopsies before and after PARPi therapy revealed that STAT3 activity was significantly higher in tumor cells and tumor-associated immune cells and fibroblasts post PARPi treatment. Moreover, one-time PARPi treatment activated STAT3 both in tumor cells as well as diverse immune subsets and fibroblasts. PARPi-treated immune cells exhibited decreased expression of immunostimulatory interferon (IFN)-γ and Granzyme B while increasing immunosuppressive cytokine IL-10. Finally, we demonstrate that the acquisition of PARPi resistance in ovarian cancer cells was accompanied by increased STAT3 activity. Ablating STAT3 inhibited PARPi-resistant ovarian tumor cell growth and/or restored PARPi sensitivity. Therefore, our study has identified a critical mechanism intrinsic to PARPi that promotes resistance to PARPi and induces immunosuppression during PARPi treatment by activating STAT3 in tumor cells and tumor-associated immune cells/fibroblasts.
Identifiants
pubmed: 34956861
doi: 10.3389/fonc.2021.724104
pmc: PMC8693573
doi:
Types de publication
Journal Article
Langues
eng
Pagination
724104Informations de copyright
Copyright © 2021 Martincuks, Song, Kohut, Zhang, Li, Zhao, Mak, Rodriguez-Rodriguez, Yu and Cristea.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Int J Gynecol Cancer. 2015 Mar;25(3):484-92
pubmed: 25594147
Curr Protoc Immunol. 2008 Nov;Chapter 14:Unit 14.1
pubmed: 19016445
Cancers (Basel). 2019 Dec 19;12(1):
pubmed: 31861720
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Cancer Res. 2007 Jun 1;67(11):5479-88
pubmed: 17545630
Nat Med. 2010 Dec;16(12):1421-8
pubmed: 21102457
Cancer Cell. 2014 Aug 11;26(2):207-21
pubmed: 25065853
Curr Opin Immunol. 2003 Oct;15(5):533-43
pubmed: 14499262
Br J Cancer. 2016 Aug 9;115(4):431-41
pubmed: 27415012
Clin Cancer Res. 2006 Sep 1;12(17):5055-63
pubmed: 16951221
Cancer Sci. 2010 Oct;101(10):2128-36
pubmed: 20860602
Cancer Res. 2016 Jul 15;76(14):4124-35
pubmed: 27216177
Cancers (Basel). 2018 Oct 29;10(11):
pubmed: 30380628
Mol Cell Biol. 2000 Oct;20(20):7450-9
pubmed: 11003642
Nat Rev Cancer. 2009 Nov;9(11):798-809
pubmed: 19851315
Ann Oncol. 2019 Sep 1;30(9):1437-1447
pubmed: 31218365
Science. 2000 Nov 17;290(5495):1354-8
pubmed: 11082062
Blood. 2017 Dec 28;130(26):2848-2859
pubmed: 29042365
Nat Cancer. 2021 Jan;2(1):66-82
pubmed: 33738458
Am J Cancer Res. 2019 Apr 01;9(4):800-815
pubmed: 31106005
Nat Rev Immunol. 2007 Jan;7(1):41-51
pubmed: 17186030
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Cancer Res. 2010 Aug 15;70(16):6467-76
pubmed: 20682796
Cancer Immunol Res. 2015 Oct;3(10):1165-74
pubmed: 25968456
Oncogene. 2012 May 3;31(18):2309-22
pubmed: 21909139
Hum Mutat. 2014 Jun;35(6):756-65
pubmed: 24700732
PLoS One. 2013;8(1):e54029
pubmed: 23326565
Nat Med. 2005 Dec;11(12):1314-21
pubmed: 16288283
NPJ Syst Biol Appl. 2017 Mar 6;3:8
pubmed: 28649435
Cancer Immunol Res. 2019 Jan;7(1):136-149
pubmed: 30401677
Immunotherapy. 2011 Apr;3(4 Suppl):23-6
pubmed: 21524164
Mol Cancer. 2020 Sep 24;19(1):145
pubmed: 32972405
Oncogene. 2017 Jan 12;36(2):168-181
pubmed: 27292260
Mol Oncol. 2013 Jun;7(3):567-79
pubmed: 23415752
Cancer Lett. 2018 Aug 1;428:117-126
pubmed: 29653268
Int J Biol Sci. 2019 Jan 24;15(3):668-679
pubmed: 30745853
Clin Cancer Res. 2011 Sep 15;17(18):6083-96
pubmed: 21795409
PLoS Pathog. 2019 Jun 21;15(6):e1007835
pubmed: 31226168
J Exp Clin Cancer Res. 2019 Jun 24;38(1):274
pubmed: 31234944
Cell Cycle. 2012 Jan 15;11(2):367-76
pubmed: 22189713
Mol Cell Biol. 2001 Oct;21(19):6615-25
pubmed: 11533249
Cancer Lett. 2013 Dec 1;341(2):231-9
pubmed: 23962558
Cancer Discov. 2019 Jun;9(6):722-737
pubmed: 31015319
BMC Cancer. 2008 Oct 21;8:302
pubmed: 18939993
J Biol Chem. 1998 Mar 13;273(11):6132-8
pubmed: 9497331
Nat Commun. 2020 Jul 24;11(1):3726
pubmed: 32709856
Trends Cell Biol. 2019 Oct;29(10):820-834
pubmed: 31421928
Cell. 2016 May 19;165(5):1092-1105
pubmed: 27133165
Lancet Oncol. 2019 Oct;20(10):1409-1419
pubmed: 31474354
Target Oncol. 2018 Dec;13(6):801-808
pubmed: 30456461
Cancer Cell. 2012 May 15;21(5):642-654
pubmed: 22624714
Nature. 2008 Feb 28;451(7182):1116-20
pubmed: 18264087
Immunity. 2016 Apr 19;44(4):913-923
pubmed: 27096320
J Immunol. 2004 Jan 1;172(1):464-74
pubmed: 14688356
Cancer Res. 2004 May 15;64(10):3550-8
pubmed: 15150111
Trends Pharmacol Sci. 2016 Jan;37(1):47-61
pubmed: 26576830
Curr Opin Oncol. 2013 Nov;25(6):637-45
pubmed: 24076584
Cancer Res. 2009 Aug 15;69(16):6381-6
pubmed: 19654294
J Clin Invest. 2011 Jul;121(7):2723-35
pubmed: 21633165
Nat Rev Clin Oncol. 2019 Feb;16(2):81-104
pubmed: 30356138
Clin Cancer Res. 2020 Jun 1;26(11):2452-2456
pubmed: 32066627
Oncotarget. 2017 Aug 10;8(44):76843-76856
pubmed: 29100353