PARP Inhibition Activates STAT3 in Both Tumor and Immune Cells Underlying Therapy Resistance and Immunosuppression In Ovarian Cancer

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Dec 27

PMID 34956861

Citations 14

Authors

Antons Martincuks

Jieun Song

Adrian Kohut

Chunyan Zhang

Yi-Jia Li

Qianqian Zhao

Edward Mak

Lorna Rodriguez-Rodriguez

Hua Yu

Mihaela Cristea

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Synthesis of a celastrol derivative as a cancer stem cell inhibitor through regulation of the STAT3 pathway for treatment of ovarian cancer.

Liu M, Li N, Wang Z, Wang S, Ren S, Li X RSC Med Chem. 2024; .

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The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities.

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The emerging role of circular RNAs in cisplatin resistance in ovarian cancer: From molecular mechanism to future potential.

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Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer.

Martincuks A, Zhang C, Austria T, Li Y, Huang R, Lugo Santiago N J Immunother Cancer. 2024; 12(4).

PMID: 38580335 PMC: 11002370. DOI: 10.1136/jitc-2023-007716.

References

Kunos C, Deng W, Dawson D, Lea J, Zanotti K, Gray H . A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study. Int J Gynecol Cancer. 2015; 25(3):484-92. PMC: 4336206. DOI: 10.1097/IGC.0000000000000380. View

Zhang X, Goncalves R, Mosser D . The isolation and characterization of murine macrophages. Curr Protoc Immunol. 2008; Chapter 14:14.1.1-14.1.14. PMC: 2834554. DOI: 10.1002/0471142735.im1401s83. View

Wu C, Sundararajan V, Sheu B, Huang R, Wei L . Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity. Cancers (Basel). 2019; 12(1). PMC: 7017004. DOI: 10.3390/cancers12010024. View

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View

Bharadwaj U, Li M, Zhang R, Chen C, Yao Q . Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. Cancer Res. 2007; 67(11):5479-88. DOI: 10.1158/0008-5472.CAN-06-3963. View

Lee H, Deng J, Kujawski M, Yang C, Liu Y, Herrmann A . STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010; 16(12):1421-8. PMC: 3088498. DOI: 10.1038/nm.2250. View

Lee H, Zhuang G, Cao Y, Du P, Kim H, Settleman J . Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014; 26(2):207-21. DOI: 10.1016/j.ccr.2014.05.019. View

Trapani J, Sutton V . Granzyme B: pro-apoptotic, antiviral and antitumor functions. Curr Opin Immunol. 2003; 15(5):533-43. DOI: 10.1016/s0952-7915(03)00107-9. View

Vaidyanathan A, Sawers L, Gannon A, Chakravarty P, Scott A, Bray S . ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells. Br J Cancer. 2016; 115(4):431-41. PMC: 4985349. DOI: 10.1038/bjc.2016.203. View

10.

Duan Z, Foster R, Bell D, Mahoney J, Wolak K, Vaidya A . Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 2006; 12(17):5055-63. DOI: 10.1158/1078-0432.CCR-06-0861. View

11.

Takaishi K, Komohara Y, Tashiro H, Ohtake H, Nakagawa T, Katabuchi H . Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010; 101(10):2128-36. PMC: 11159803. DOI: 10.1111/j.1349-7006.2010.01652.x. View

12.

Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W . FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling. Cancer Res. 2016; 76(14):4124-35. DOI: 10.1158/0008-5472.CAN-15-2973. View

13.

Dasari S, Fang Y, Mitra A . Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression. Cancers (Basel). 2018; 10(11). PMC: 6265896. DOI: 10.3390/cancers10110406. View

14.

Arizti P, Fang L, Park I, Yin Y, Solomon E, Ouchi T . Tumor suppressor p53 is required to modulate BRCA1 expression. Mol Cell Biol. 2000; 20(20):7450-9. PMC: 86298. DOI: 10.1128/MCB.20.20.7450-7459.2000. View

15.

Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009; 9(11):798-809. PMC: 4856025. DOI: 10.1038/nrc2734. View

16.

Mateo J, Lord C, Serra V, Tutt A, Balmana J, Castroviejo-Bermejo M . A decade of clinical development of PARP inhibitors in perspective. Ann Oncol. 2019; 30(9):1437-1447. PMC: 6771225. DOI: 10.1093/annonc/mdz192. View

17.

Badovinac V, Tvinnereim A, Harty J . Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science. 2000; 290(5495):1354-8. DOI: 10.1126/science.290.5495.1354. View

18.

Nieborowska-Skorska M, Maifrede S, Dasgupta Y, Sullivan K, Flis S, Le B . Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017; 130(26):2848-2859. PMC: 5746670. DOI: 10.1182/blood-2017-05-784942. View

19.

Mehta A, Cheney E, Hartl C, Pantelidou C, Oliwa M, Castrillon J . Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer. 2021; 2(1):66-82. PMC: 7963404. DOI: 10.1038/s43018-020-00148-7. View

20.

Han Y, Li C, Hsu J, Hsu J, Chan L, Tan X . Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 upregulation in triple-negative breast cancer. Am J Cancer Res. 2019; 9(4):800-815. PMC: 6511636. View