Loading

Editorial Open Access
Volume 1 | Issue 1 | DOI: https://doi.org/10.33696/immunology.1.001

Deubiquitinase as Potential Targets for Cancer Immunotherapy

  • 1Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston TX 77030, USA
+ Affiliations - Affiliations

*Corresponding Author

Xiaoping Xie, xxie5@mdanderson.org

Received Date: January 27, 2019

Accepted Date: January 28, 2019

Introduction

During the last few decades, immunotherapy is considered to be an important approach to help our immune system to fight various kinds of diseases, such as tumor [1,2]. Sometimes, it works very well for some types of cancers, for example: bladder cancer [3], colorectal cancer [4], breast cancer [5,6] and lymphoma [7]. Especially, when patients fail of traditional radiation and chemotherapy treatment. Several kinds of immunotherapy strategies are being applied to treat cancer, including monoclonal antibodies; immune checkpoint inhibitors; cancer vaccines and non-specific immunotherapies. Deubiquitinase (DUB) have been well recognized as important regulators for innate and adaptive immune responses and as potential therapeutic targets for the treatment of cancer diseases [8,9]. Moreover, several small molecules specific targeted on DUBs have been discovered and developed for the treatment of various types of cancer [10].

Regulation of Innate Immune Response by DUBs

Dendritic cells, a major type of innate immune cells involved in the regulation of T cell activation, inflammation, as well as tumor microenvironment [11], is considered to be a potent mediator bridging the innate and adaptive immune systems [12,13]. It could uptake and present the tumour-specific antigens to activate CD4+ or CD8+ T cell response [14]. Recent studies reported an unexpected role for a deubiquitinase, Trabid, in regulating TLR signaling in dendritic cells, driving inflammatory T cell responses and demonstrated, for the first time, an epigenetic mechanism that mediates NF-κB activation and induction of the IL12 and IL23 proinflammatory cytokine genes by TLRs. This mechanism involves

Trabid-mediated deubiquitination and stabilization of the demethylase Jmjd2d, which in turn “erases” repressive histone methylation marks at IL12and IL23 promoters [15]. Furthermore, another deubiquitinase, Mysm1, could regulate the steady-state DC development via epigenetically regulate Flt3 promoter region [16]. Moreover, deubiquitinase A20 acted on the regulation of DC maturation and activation, then maintained these cells in tolerance status. Depletion of A20 in dendritic cells could increase their antigen presentation ability and promote Th1 and Th17 differentiation [17].

Regulation of T cell Activation by DUBs

Activation of antigen-specific T cell response is critical for the treatment of cancer and viral diseases [18-21]. The activated antigen specific effector T cells could migrate into inflammation or tumor deposits through lymph node [22]. Therefore, modulation of immune response could benefit the treatment of cancer immunotherapy [23]. Ubiquitination, as the pivotal posttranslational modification, is an important player in the regulation of T cell development, homeostasis and activation [24,25]. Recently, Otud7b, an OUT family of DUB, was identified as pivotal regulator of TCR proximal signaling [26]. In addition, depletion of Otud7b impaired the activation of TCR downstream signaling factors Zap70 and refractory to T cell-mediated autoimmunity and inflammation. Moreover, DUBs also could modulate T cell activation through an indirect regulation of the regulatory T cells (Tregs). Recent studies demonstrated that USP7, a deubiquitinating enzyme, could enhance the stability and function of Tregs. Interestingly, pharmacological inhibition or knockdown of USP7 impaired their inhibitory function along with T cell activation [27].

DUBs Inhibitors on Cancer Immunotherapy

The FDA approved Velcade (bortezomib), a 26S proteasome inhibitor, to be used for the treatment of hematologic and solid-organ malignancies, which indicating the potential roles of Ubiquitin proteasome system in fighting tumor [28]. In addition, another proteasome inhibitor Kyprolis (carfilzomib), was approved for the treatment of multiple myeloma in 2012 [29]. Unfortunately, some patients showed resistant or develop resistance during the treatment with these inhibitors. Also, due to the non-specific target of these inhibitors result in high toxic effects.

In the meantime, more specific inhibitors targeting upstream molecules of the ubiquitin proteasome system become more promising and have been investigated as potential targets for tumor therapy [30-32].

Inhibition of single or multiple DUBs by synthetic small molecule inhibitors has attracted pharmacological companies and research institutes’ interest. Inhibition of USP14 leads to increased degradation of oxidized proteins and benefit to reduce aberrant proteins under stress condition [33]. Thus, the DUBs inhibitor IU1 showed potential promising effects on the therapeutic benefits of Alzheimer’s disease. With high throughput screening approaches, Dr. Chen and his colleagues identified selective small molecule inhibitors (Pimozide and GW7647) targeting at human USP1/UAF1. They also demonstrated that these inhibitors could synergize with traditional drug cisplatin in the treatment of non-small cell lung cancer cells [34].

USP7 plays critical roles in the regulation of cell cycle along with tumor suppressors and oncogenes. Therefore, it has great possibility as a novel therapeutic target for cancer therapy. Reverdy et al. identified selective small molecule inhibitors against USP7 through biochemical assay and activity-based protein profiling in living systems and reported that cell proliferation and cell cycle was altered by the treatment of USP7 inhibitors, which indicated that USP7 is a promising therapeutic target for cancer therapy [35].

Conclusion

Deubiquitinase plays pivotal roles in the regulation of immune response along with cell proliferation and cell cycle, which draws increased attention to be used as novel strategies for cancer patients. Translational studies using pharmacological DUBs inhibitors suggest that targeting DUBs to modulate immune response along with directly induce its apoptosis, will lead to promising therapeutic opportunities in clinical application.

References

1. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer?. BMC medicine. 2016 Dec; 14(1):73.

2. Wraith DC. the Future of immunotherapy: A 20-Year Perspective. Frontiers in immunology. 2017 Nov 28; 8:1668.

3. Lamm DL, Thor DE, Stogdill VD, Radwin HM. Bladder cancer immunotherapy. The Journal of urology. 1982 Nov 1; 128(5):931-5.

4. Boland P, Ma W. Immunotherapy for colorectal cancer. Cancers. 2017; 9(5):50.

5. Williams AD, Payne KK, Posey AD, Hill C, Conejo- Garcia J, June CH, et al. Immunotherapy for Breast Cancer: Current and Future Strategies. Current surgery reports. 2017 Dec 1; 5(12):31.

6. Zhang P, Xiao Z, Wang S, Zhang M, Wei Y, Hang Q, et al. ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. Cell reports. 2018 Apr 17; 23(3):823-37.

7. Bair SM, Mato A, Svoboda J. Immunotherapy for the Treatment of Hodgkin Lymphoma: An Evolving Paradigm. Clinical Lymphoma Myeloma and Leukemia. 2018 Mar 31; 18(6):380-91.

8. Bednash JS, Mallampalli RK. Targeting deubiquitinases in cancer. InProteases and Cancer. Humana Press, New York, NY. 2018; 1731:295-305.

9. Singh N, Singh AB. Deubiquitinases and cancer: a snapshot. Critical reviews in oncology/hematology. 2016 Jul 1; 103:22-6.

10. D'arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacology & therapeutics. 2015 Mar 1; 147:32-54.

11. Shi JH, Xie X, Sun SC. TBK1 as a regulator of autoimmunity and antitumor immunity. Cellular & molecular immunology. 2018 Mar 5; 15(8):743-45.

12. Li J, Geng S, Xie X, Liu H, Zheng G, Sun X, et al. Caveolin-1–mediated negative signaling plays a critical role in the induction of regulatory dendritic cells by DNA and protein coimmunization. The Journal of Immunology. 2012 Aug 17:1102828.

13. Geng S, Zhang H, Zhou X, He Y, Zhang X, Xie X, et al. Diabetes tolerogenic vaccines targeting antigen-specific inflammation. Human vaccines & immunotherapeutics. 2015 Feb 1; 11(2):522-30.

14. Xiao Y, Zou Q, Xie X, Liu T, Li HS, Jie Z, et al. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. Journal of Experimental Medicine. 2017 May 1;214(5):1493-507.

15. Jin J, Xie X, Xiao Y, Hu H, Zou Q, Cheng X, et al. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nature immunology. 2016 Mar; 17(3):259.

16. Won H, Nandakumar V, Yates P, Sanchez S, Jones L, Huang XF, et al. Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1. Blood. 2014 Jan 1:blood-2013.

17. Kool M, van Loo G, Waelput W, De Prijck S, Muskens F, Sze M, et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity. 2011 Jul 22; 35(1):82-96.

18. Liu H, Geng S, Feng C, Xie X, Wu B, Chen X, et al. A DNA vaccine targeting p42. 3 induces protective antitumor immunity via eliciting cytotoxic CD8+ T lymphocytes in a murine melanoma model. Human vaccines & immunotherapeutics. 2013 Oct 4; 9(10):2196- 202.

19. Xie X, Geng S, Liu H, Li C, Yang Y, Wang B. Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8+ T cell. Human vaccines & immunotherapeutics. 2014 Jun 4; 10(6):1688-99.

20. Geng S, Zhong Y, Wang S, Liu H, Zou Q, Xie X, et al.Amiloride enhances antigen specific CTL by faciliting HBV DNA vaccine entry into cells. PloS one. 2012 Mar 16; 7(3):e33015.

21. Zou Q, Hu Y, Xue J, Fan X, Jin Y, Shi X, et al. Use of praziquantel as an adjuvant enhances protection and Tc- 17 responses to killed H5N1 virus vaccine in mice. PloS one. 2012 Apr 18; 7(4):e34865.

22. Geng S, Zhong Y, Zhou X, Zhao G, Xie X, Pei Y, et al. induced regulatory T cells superimpose Their suppressive capacity with effector T cells in lymph nodes via antigenspecific s1p1-Dependent egress Blockage. Frontiers in immunology. 2017 Jun 7; 8:663.

23. Weng J, Moriarty KE, Baio FE, Chu F, Kim SD, He J, et al. IL-15 enhances the antitumor effect of human antigen-specific CD8+ T cells by cellular senescence delay. Oncoimmunology. 2016 Dec 1; 5(12):e1237327.

24. Ebner P, Versteeg GA, Ikeda F. Ubiquitin enzymes in the regulation of immune responses. Critical reviews in biochemistry and molecular biology. 2017 Jul 4; 52(4):425-60.

25. Zou Q, Jin J, Xiao Y, Hu H, Zhou X, Jie Z, et al. T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi. Journal of Experimental Medicine. 2015 Jul 27; 212(8):1323-36.

26. Hu H, Wang H, Xiao Y, Jin J, Chang JH, Zou Q, et al. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. Journal of experimental medicine. 2016 Mar 7;213(3):399-414.

27. van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE, et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity. 2013 Aug 22; 39(2):259-71.

28. Bold R. “Development of the Proteasome Inhibitor Velcade™(Bortezomib)” by Julian Adams, Ph. D., and Michael Kauffman, MD, Ph. D. Cancer Investigation, 2009; 22(2):328-29.

29. Steele JM. Carfilzomib: a new proteasome inhibitor for relapsed or refractory multiple myeloma. Journal of oncology pharmacy practice. 2013 Dec; 19(4):348-54.

30. Sampath D. Targeting deubiquitinases in CLL. Blood. 2017 Jul 13; 130(2):100-1.

31. Harrigan JA, Jacq X, Martin NM, Jackson SP. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nature Reviews Drug Discovery. 2018 Jan; 17(1):57.

32. Rape M. Ubiquitylation at the crossroads of development and disease. Nature Reviews Molecular Cell Biology. 2018 Jan; 19(1):59.

33. Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010 Sep; 467(7312):179.

34. Chen J, Dexheimer TS, Ai Y, Liang Q, Villamil MA, Inglese J, et al. Selective and cell-active inhibitors of the USP1/UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chemistry & biology. 2011 Nov 23; 18(11):1390-400.

35. Reverdy C, Conrath S, Lopez R, Planquette C, Atmanene C, Collura V, et al. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chemistry & biology. 2012 Apr 20; 19(4):467-77.

Author Information X