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SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma

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Abstract

Purpose

High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research.

Methods

SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF).

Results

We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models.

Conclusions

This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. A.B. El-Khoueiry, B. Sangro, T. Yau, T.S. Crocenzi, M. Kudo, C. Hsu, T.Y. Kim, S.P. Choo, J. Trojan, T.H.R. Welling, T. Meyer, Y.K. Kang, W. Yeo, A. Chopra, J. Anderson, C. Dela Cruz, L. Lang, J. Neely, H. Tang, H.B. Dastani, I. Melero, Lancet 389, 2492–2502 (2017). https://doi.org/10.1016/S0140-6736(17)31046-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Y. Zhu, J. Yang, D. Xu, X.M. Gao, Z. Zhang, J.L. Hsu, C.W. Li, S.O. Lim, Y.Y. Sheng, Y. Zhang, J.H. Li, Q. Luo, Y. Zheng, Y. Zhao, L. Lu, H.L. Jia, M.C. Hung, Q.Z. Dong, L.X. Qin, Gut 68, 1653–1666 (2019). https://doi.org/10.1136/gutjnl-2019-318419

    Article  CAS  PubMed  Google Scholar 

  3. C. Lu, D. Rong, B. Zhang, W. Zheng, X. Wang, Z. Chen, W. Tang, Mol. Cancer 18, 130 (2019). https://doi.org/10.1186/s12943-019-1047-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. M. Xie, J. Yu, S. Ge, J. Huang, X. Fan, Cancer Lett. 469, 301–309 (2020). https://doi.org/10.1016/j.canlet.2019.11.004

    Article  CAS  PubMed  Google Scholar 

  5. A. Kukkula, V.K. Ojala, L.M. Mendez, L. Sistonen, K. Elenius, M. Sundvall, Cancers 13, (2021). https://doi.org/10.3390/cancers13174402

  6. X. Zhao, Mol. Cell 71, 409–418 (2018). https://doi.org/10.1016/j.molcel.2018.07.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. W. Zhao, X.Y. Zhang, J.H. Rong, Front. Cardiovasc. Med. 8, ARTN 701583 (2018). https://doi.org/10.3389/fcvm.2021.701583

    Article  CAS  Google Scholar 

  8. G. Bossis, F. Melchior, Mol. Cell 21, 349–357 (2006). https://doi.org/10.1016/j.molcel.2005.12.019

    Article  CAS  PubMed  Google Scholar 

  9. P. Sarangi, X. Zhao, Trends Biochem. Sci. 40, 233–242 (2015). https://doi.org/10.1016/j.tibs.2015.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. A. Decque, O. Joffre, J.G. Magalhaes, J.C. Cossec, R. Blecher-Gonen, P. Lapaquette, A. Silvin, N. Manel, P.E. Joubert, J.S. Seeler, M.L. Albert, I. Amit, S. Amigorena, A. Dejean, Nat. Immunol. 17, 140–149 (2016). https://doi.org/10.1038/ni.3342

    Article  CAS  PubMed  Google Scholar 

  11. J.T. Crowl, D.B. Stetson, Proc. Natl. Acad. Sci. U. S. A. 115, 6798–6803 (2018). https://doi.org/10.1073/pnas.1802114115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. I.A. Hendriks, A.C. Vertegaal, Nat. Rev. Mol. Cell Biol. 17, 581–595 (2016). https://doi.org/10.1038/nrm.2016.81

    Article  CAS  PubMed  Google Scholar 

  13. S.J. Moschos, D.M. Jukic, C. Athanassiou, R. Bhargava, S. Dacic, X. Wang, S.F. Kuan, S.L. Fayewicz, C. Galambos, M. Acquafondata, R. Dhir, D. Becker, Hum. Pathol. 41, 1286–1298 (2010). https://doi.org/10.1016/j.humpath.2010.02.007

    Article  CAS  PubMed  Google Scholar 

  14. M. Zeng, W. Liu, Y. Hu, N. Fu, Clin. Chim. Acta 510, 347–353 (2020). https://doi.org/10.1016/j.cca.2020.07.044

    Article  CAS  PubMed  Google Scholar 

  15. H. Yuan, Y. Lu, Y.T. Chan, C. Zhang, N. Wang, Y. Feng, Cancers 13, (2021). https://doi.org/10.3390/cancers13225700

  16. H. Xu, H. Wang, W. Zhao, S. Fu, Y. Li, W. Ni, Y. Xin, W. Li, C. Yang, Y. Bai, M. Zhan, L. Lu, Theranostics 10, 5671–5686 (2020). https://doi.org/10.7150/thno.42539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. I. Zubiete-Franco, J.L. Garcia-Rodriguez, F. Lopitz-Otsoa, M. Serrano-Macia, J. Simon, P. Fernandez-Tussy, L. Barbier-Torres, D. Fernandez-Ramos, V. Gutierrez-de-Juan, S. Lopez de Davalillo, O. Carlevaris, A. Beguiristain Gomez, E. Villa, D. Calvisi, C. Martin, E. Berra, P. Aspichueta, N. Beraza, M. Varela-Rey, M. Avila, M.S. Rodriguez, J.M. Mato, I. Diaz-Moreno, A. Diaz-Quintana, T.C. Delgado, M.L. Martinez-Chantar, EBioMedicine 40, 406–421 (2019). https://doi.org/10.1016/j.ebiom.2018.12.031

    Article  PubMed  Google Scholar 

  18. X. He, J. Riceberg, T. Soucy, E. Koenig, J. Minissale, M. Gallery, H. Bernard, X. Yang, H. Liao, C. Rabino, P. Shah, K. Xega, Z.H. Yan, M. Sintchak, J. Bradley, H. Xu, M. Duffey, D. England, H. Mizutani, Z. Hu, J. Guo, R. Chau, L.R. Dick, J.E. Brownell, J. Newcomb, S. Langston, E.S. Lightcap, N. Bence, S.M. Pulukuri, Nat. Chem. Biol. 13, 1164–1171 (2017). https://doi.org/10.1038/nchembio.2463

    Article  CAS  PubMed  Google Scholar 

  19. S.P. Langston, S. Grossman, D. England, R. Afroze, N. Bence, D. Bowman, N. Bump, R. Chau, B.C. Chuang, C. Claiborne, L. Cohen, K. Connolly, M. Duffey, N. Durvasula, S. Freeze, M. Gallery, K. Galvin, J. Gaulin, R. Gershman, P. Greenspan, J. Grieves, J. Guo, N. Gulavita, S. Hailu, X. He, K. Hoar, Y. Hu, Z. Hu, M. Ito, M.S. Kim, S.W. Lane, D. Lok, A. Lublinsky, W. Mallender, C. McIntyre, J. Minissale, H. Mizutani, M. Mizutani, N. Molchinova, K. Ono, A. Patil, M. Qian, J. Riceberg, V. Shindi, M.D. Sintchak, K. Song, T. Soucy, Y. Wang, H. Xu, X. Yang, A. Zawadzka, J. Zhang, S.M. Pulukuri, J. Med. Chem. 64, 2501–2520 (2021). https://doi.org/10.1021/acs.jmedchem.0c01491

    Article  CAS  PubMed  Google Scholar 

  20. L.M. Weber, M.D. Robinson, Cytometry A 89, 1084–1096 (2016). https://doi.org/10.1002/cyto.a.23030

    Article  CAS  PubMed  Google Scholar 

  21. Z. Gu, L. Gu, R. Eils, M. Schlesner, B. Brors, Bioinformatics 30, 2811–2812 (2014). https://doi.org/10.1093/bioinformatics/btu393

    Article  CAS  PubMed  Google Scholar 

  22. M. Nowicka, C. Krieg, H.L. Crowell, L.M. Weber, F.J. Hartmann, S. Guglietta, B. Becher, M.P. Levesque, M.D. Robinson, F1000Res 6, 748 (2017). https://doi.org/10.12688/f1000research.11622.3

    Article  PubMed  Google Scholar 

  23. B. Melit Devassy, S. George, P. Nussbaum, J. Imaging 6, (2020). https://doi.org/10.3390/jimaging6050029

  24. M.H. Spitzer, P.F. Gherardini, G.K. Fragiadakis, N. Bhattacharya, R.T. Yuan, A.N. Hotson, R. Finck, Y. Carmi, E.R. Zunder, W.J. Fantl, S.C. Bendall, E.G. Engleman, G.P. Nolan, Science 349, 1259425 (2015). https://doi.org/10.1126/science.1259425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. N. Samusik, Z. Good, M.H. Spitzer, K.L. Davis, G.P. Nolan, Nat. Methods 13, 493–496 (2016). https://doi.org/10.1038/nmeth.3863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Y. Cheng, M.T. Wong, L. van der Maaten, E.W. Newell, J. Immunol. 196, 924–932 (2016). https://doi.org/10.4049/jimmunol.1501928

    Article  CAS  PubMed  Google Scholar 

  27. M.T. Amith, K. Fujimoto, C. Tao, HCI Int. 2019 Posters (2019) 1034, 3–12 (2019). https://doi.org/10.1007/978-3-030-23525-3_1

    Article  PubMed  Google Scholar 

  28. F. Hahne, N. LeMeur, R.R. Brinkman, B. Ellis, P. Haaland, D. Sarkar, J. Spidlen, E. Strain, R. Gentleman, BMC Bioinformatics 10, 106 (2009). https://doi.org/10.1186/1471-2105-10-106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. G. Finak, W. Jiang, J. Pardo, A. Asare, R. Gottardo, BMC Bioinformatics 13, 252 (2012). https://doi.org/10.1186/1471-2105-13-252

    Article  PubMed  PubMed Central  Google Scholar 

  30. S.A. Ismail, S. El Saadany, D.H. Ziada, S.S. Zakaria, W.W. Mayah, H. Elashry, M. Arafa, N. Elmashad, Asian Pac. J. Cancer Prev.: APJCP 18, 1105–1111 (2017). https://doi.org/10.22034/APJCP.2017.18.4.1105

    Article  PubMed  PubMed Central  Google Scholar 

  31. G. Schicht, L. Seidemann, R. Haensel, D. Seehofer, G. Damm, Cancers 14, (2022). https://doi.org/10.3390/cancers14174227

  32. V. Mitsialis, S. Wall, P. Liu, J. Ordovas-Montanes, T. Parmet, M. Vukovic, D. Spencer, M. Field, C. McCourt, J. Toothaker, A. Bousvaros, C. Boston Children’s Hospital Inflammatory Bowel Disease, Brigham, C.s. Women’s Hospital, C. Colitis, A.K. Shalek, L. Kean, B. Horwitz, J. Goldsmith, G. Tseng, S.B. Snapper, L. Konnikova, Gastroenterology 159, 591-608 e510 (2020). https://doi.org/10.1053/j.gastro.2020.04.074

    Article  CAS  PubMed  Google Scholar 

  33. S. Van Gassen, B. Callebaut, M.J. Van Helden, B.N. Lambrecht, P. Demeester, T. Dhaene, Y. Saeys, Cytometry A 87, 636–645 (2015). https://doi.org/10.1002/cyto.a.22625

    Article  PubMed  Google Scholar 

  34. L. Zhang, X. Yu, L. Zheng, Y. Zhang, Y. Li, Q. Fang, R. Gao, B. Kang, Q. Zhang, J.Y. Huang, H. Konno, X. Guo, Y. Ye, S. Gao, S. Wang, X. Hu, X. Ren, Z. Shen, W. Ouyang, Z. Zhang, Nature 564, 268–272 (2018). https://doi.org/10.1038/s41586-018-0694-x

    Article  CAS  PubMed  Google Scholar 

  35. A. El Motiam, S. Vidal, R. Seoane, Y.H. Bouzaher, J. Gonzalez-Santamaria, C. Rivas, Adv. Exp. Med. Biol. 1233, 263–277 (2020). https://doi.org/10.1007/978-3-030-38266-7_11

    Article  CAS  PubMed  Google Scholar 

  36. E.S. Lightcap, P. Yu, S. Grossman, K. Song, M. Khattar, K. Xega, X. He, J.M. Gavin, H. Imaichi, J.J. Garnsey, E. Koenig, H. Zhang, Z. Lu, P. Shah, Y. Fu, M.A. Milhollen, B.A. Hatton, J. Riceberg, V. Shinde, C. Li, J. Minissale, X. Yang, D. England, R.A. Klinghoffer, S. Langston, K. Galvin, G. Shapiro, S.M. Pulukuri, S.Y. Fuchs, D. Huszar, Sci. Transl. Med. 13, eaba7791 (2021). https://doi.org/10.1126/scitranslmed.aba7791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. R. Zappasodi, I. Serganova, I.J. Cohen, M. Maeda, M. Shindo, Y. Senbabaoglu, M.J. Watson, A. Leftin, R. Maniyar, S. Verma, M. Lubin, M. Ko, M.M. Mane, H. Zhong, C. Liu, A. Ghosh, M. Abu-Akeel, E. Ackerstaff, J.A. Koutcher, P.C. Ho, G.M. Delgoffe, R. Blasberg, J.D. Wolchok, T. Merghoub, Nature 591, 652–658 (2021). https://doi.org/10.1038/s41586-021-03326-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. A.E. Overacre-Delgoffe, D.A.A. Vignali, Cancer Immunol. Res. 6, 882–887 (2018). https://doi.org/10.1158/2326-6066.Cir-18-0066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. J. Behary, N. Amorim, X.T. Jiang, A. Raposo, L. Gong, E. McGovern, R. Ibrahim, F. Chu, C. Stephens, H. Jebeili, V. Fragomeli, Y.C. Koay, M. Jackson, J. O’Sullivan, M. Weltman, G. McCaughan, E. El-Omar, A. Zekry, Nat. Commun. 12, 187 (2021). https://doi.org/10.1038/s41467-020-20422-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. A. Tripathi, J. Debelius, D.A. Brenner, M. Karin, R. Loomba, B. Schnabl, R. Knight, Nat. Rev. Gastroenterol. Hepatol. 15, 397–411 (2018). https://doi.org/10.1038/s41575-018-0011-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. S. Verma, G. Mohapatra, S.M. Ahmad, S. Rana, S. Jain, J.K. Khalsa, C.V. Srikanth, Mol. Cell. Biol. 35, 2932–2946 (2015). https://doi.org/10.1128/mcb.00397-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. B. Pan, Z. Chen, X. Zhang, Z. Wang, Y. Yao, X. Wu, J. Qiu, H. Lin, L. Yu, H. Tu, N. Tang, J. Immunother. Cancer 11, (2023). https://doi.org/10.1136/jitc-2023-006817

  43. N. Segata, J. Izard, L. Waldron, D. Gevers, L. Miropolsky, W.S. Garrett, C. Huttenhower, Genome Biol. 12, R60 (2011). https://doi.org/10.1186/gb-2011-12-6-r60

    Article  PubMed  PubMed Central  Google Scholar 

  44. J. Liu, X. Li, F. Song, S. Cui, W. Lu, J. Zhao, H. Zhang, Z. Gu, W. Chen, Food Res. Int. 151, 110858 (2022). https://doi.org/10.1016/j.foodres.2021.110858

    Article  CAS  PubMed  Google Scholar 

  45. E.A. Kennedy, K.Y. King, M.T. Baldridge, Front. Physiol. 9, 1534 (2018). https://doi.org/10.3389/fphys.2018.01534

    Article  PubMed  PubMed Central  Google Scholar 

  46. S. Kumar, M.J.A. Schoonderwoerd, J.S. Kroonen, I.J. de Graaf, M. Sluijter, D. Ruano, R. Gonzalez-Prieto, M. Verlaan-de Vries, J. Rip, R. Arens, N. de Miranda, L. Hawinkels, T. van Hall, A.C.O. Vertegaal, Gut 71, 2266–2283 (2022). https://doi.org/10.1136/gutjnl-2021-324834

    Article  CAS  PubMed  Google Scholar 

  47. A. Nakamura, S. Grossman, K. Song, K. Xega, Y. Zhang, D. Cvet, A. Berger, G. Shapiro, D. Huszar, Blood 139, 2770–2781 (2022). https://doi.org/10.1182/blood.2021014267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. R. Molfetta, A. Zingoni, A. Santoni, R. Paolini, Front. Immunol. 10, 2557 (2019). https://doi.org/10.3389/fimmu.2019.02557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. L. Du, W. Liu, S.T. Rosen, Curr. Opin. Oncol. 33, 520–525 (2021). https://doi.org/10.1097/cco.0000000000000765

    Article  CAS  PubMed  Google Scholar 

  50. S. Crunkhorn, Nat. Rev. Drug Discov. 20, 816 (2021). https://doi.org/10.1038/d41573-021-00174-9

    Article  CAS  PubMed  Google Scholar 

  51. J.S. Kroonen, A.C.O. Vertegaal, Trends Cancer 7, 496–510 (2021). https://doi.org/10.1016/j.trecan.2020.11.009

    Article  CAS  PubMed  Google Scholar 

  52. R.F. Schwabe, T.F. Greten, J. Hepatol. 72, 230–238 (2020). https://doi.org/10.1016/j.jhep.2019.08.016

    Article  CAS  PubMed  Google Scholar 

  53. Z. Li, Y. Zhang, W. Hong, B. Wang, Y. Chen, P. Yang, J. Zhou, J. Fan, Z. Zeng, S. Du, Gut Microbes 14, 2119055 (2022). https://doi.org/10.1080/19490976.2022.2119055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Public Technology Service Center Fujian Medical University for their help and technical support.

Funding

This work was supported by the Key Project of Fujian Provincial Natural Science Foundation (2022J02039), the Joint Funds for the Innovation of Science and Technology, Fujian Province (2021Y9067), the National Natural Science Foundation of China (82173167), and the High-Level Medical Care Construction Foundation of Fujian Province ([2021]76).

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Author notes

  1. Zengbin Wang, Banglun Pan and Lili Su contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China

    Zengbin Wang, Lili Su & Huahui Yu

  2. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China

    Banglun Pan, Xiaoxuan Wu, Yuxin Yao, Xiaoxia Zhang, Jiacheng Qiu & Nanhong Tang

  3. Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China

    Nanhong Tang

  4. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China

    Nanhong Tang

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Contributions

Conception and design: ZW, BP and LS. Development of methodology: HY, YY and XW. Data curation: JQ and XZ. Writing, review and/or revision of the manuscript: ZW, BP and LS. Study supervision: NT.

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Correspondence to Nanhong Tang.

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Wang, Z., Pan, B., Su, L. et al. SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma. Cell Oncol. 47, 513–532 (2024). https://doi.org/10.1007/s13402-023-00880-z

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