Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma

Oncogene volume 43, pages 776–788 (2024)Cite this article

Subjects

Abstract

Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Chemoresistance can be transmitted from GEM resistant PDAC cells to GEM sensitive cells.
Fig. 2: The transmission of GEM resistance in pancreatic cancer cells is mediated by IL-35.
Fig. 3: IL-35 enhances GEM tolerance of PDAC cells.
Fig. 4: IL-35 scavenges ROS to augment PDAC cells survival.
Fig. 5: IL-35 activated SOD2 expression to eliminate GEM induced ROS.
Fig. 6: GEM activates IL-35 expression via NF-κB signaling, leading to acquired chemoresistance.
Fig. 7: Anti-il-35 neutralizing antibody can sensitize GEM and significantly inhibit tumor growth in mice model.

Similar content being viewed by others

Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA: A Cancer J Clin. 2021;71:7–33.

    Google Scholar 

  2. Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol. 2020;17:108–23.

    Article  PubMed  Google Scholar 

  3. Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–81.

    Article  CAS  PubMed  Google Scholar 

  4. Conroy T, Castan F, Lopez A, Turpin A, Ben Abdelghani M, Wei AC, et al. Five-Year Outcomes of FOLFIRINOX vs gemcitabine as adjuvant therapy for pancreatic cancer: a randomized clinical trial. JAMA Oncol. 2022;8:1571–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dalgleish AG, Stebbing J, Adamson DJ, Arif SS, Bidoli P, Chang D, et al. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br J cancer. 2016;115:789–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zheng H-C. The molecular mechanisms of chemoresistance in cancers. Oncotarget. 2017;8:59950.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wilson T, Longley D, Johnston P. Chemoresistance in solid tumours. Ann Oncol. 2006;17:x315–x324.

    Article  PubMed  Google Scholar 

  8. Samanta K, Setua S, Kumari S, Jaggi M, Yallapu MM, Chauhan SC. Gemcitabine combination nano therapies for pancreatic cancer. Pharmaceutics. 2019;11:574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Eshmuminov D, Aminjonov B, Palm RF, Malleo G, Schmocker RK, Abdallah R, et al. FOLFIRINOX or gemcitabine-based chemotherapy for borderline resectable and locally advanced pancreatic cancer: a multi-institutional, patient-level, meta-analysis and systematic review. Ann Surg Oncol. 2023;30:4417–28.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ju HQ, Gocho T, Aguilar M, Wu M, Zhuang ZN, Fu J, et al. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Mol Cancer Ther. 2015;14:788–98.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou X, An B, Lin Y, Ni Y, Zhao X, Liang X. Molecular mechanisms of ROS-modulated cancer chemoresistance and therapeutic strategies. Biomed Pharmacother. 2023;165:115036.

    Article  CAS  PubMed  Google Scholar 

  12. Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. 2019;25:101084.

    Article  CAS  PubMed  Google Scholar 

  13. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20:131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Farran B, Nagaraju GP. Exosomes as therapeutic solutions for pancreatic cancer. Drug Discov today. 2020;25:2245–56.

    Article  CAS  PubMed  Google Scholar 

  15. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–9.

    Article  CAS  PubMed  ADS  Google Scholar 

  16. Shen P, Roch T, Lampropoulou V, O’Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507:366–70.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  17. Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, et al. The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 2012;13:290–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang C, Li N, Li Z, Chang A, Chen Y, Zhao T, et al. Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression. Nat Commun. 2017;8:14035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Huang C, Li Z, Li N, Li Y, Chang A, Zhao T, et al. Interleukin 35 expression correlates with microvessel density in pancreatic ductal adenocarcinoma, recruits monocytes, and promotes growth and angiogenesis of xenograft tumors in mice. Gastroenterology. 2018;154:675–88.

    Article  CAS  PubMed  Google Scholar 

  20. Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11:1093–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mirzaei S, Mohammadi AT, Gholami MH, Hashemi F, Zarrabi A, Zabolian A, et al. Nrf2 signaling pathway in cisplatin chemotherapy: potential involvement in organ protection and chemoresistance. Pharmacol Res. 2021;167:105575.

    Article  CAS  PubMed  Google Scholar 

  22. Landriscina M, Maddalena F, Laudiero G, Esposito F. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid redox Signal. 2009;11:2701–16.

    Article  CAS  PubMed  Google Scholar 

  23. Chang A, Liu L, Ashby JM, Wu D, Chen Y, O’Neill SS, et al. Recruitment of KMT2C/MLL3 to DNA damage sites mediates DNA damage responses and regulates PARP inhibitor sensitivity in cancer. Cancer Res. 2021;81:3358–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Spratlin JL, Mackey JR. Human equilibrative nucleoside transporter 1 (hENT1) in pancreatic adenocarcinoma: towards individualized treatment decisions. Cancers. 2010;2:2044–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kohan HG, Boroujerdi M. Time and concentration dependency of P-gp, MRP1 and MRP5 induction in response to gemcitabine uptake in Capan-2 pancreatic cancer cells. Xenobiotica. 2015;45:642–52.

    Article  CAS  PubMed  Google Scholar 

  26. Azarabadi S, Abdollahi H, Torabi M, Salehi Z, Nasiri J. ROS generation, oxidative burst and dynamic expression profiles of ROS-scavenging enzymes of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) in response to Erwinia amylovora in pear (Pyrus communis L). Eur J Plant Pathol. 2017;147:279–94.

    Article  CAS  Google Scholar 

  27. Furlan-Magaril M, Rincón-Arano H, Recillas-Targa F. Sequential chromatin immunoprecipitation protocol: ChIP-reChIP. DNA-Protein Interactions: Princ Protoc, Third Ed. 2009;543:253–66.

    Article  CAS  Google Scholar 

  28. Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse M-L, Fölsch UR, et al. Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003;22:3243–51.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Z, Duan Q, Zhao H, Liu T, Wu H, Shen Q, et al. Gemcitabine treatment promotes pancreatic cancer stemness through the Nox/ROS/NF-κB/STAT3 signaling cascade. Cancer Lett. 2016;382:53–63.

    Article  CAS  PubMed  Google Scholar 

  30. Patel GK, Khan MA, Bhardwaj A, Srivastava SK, Zubair H, Patton MC, et al. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer. 2017;116:609–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fan J, Wei Q, Koay EJ, Liu Y, Ning B, Bernard PW, et al. Chemoresistance transmission via exosome-mediated EphA2 transfer in pancreatic cancer. Theranostics. 2018;8:5986–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu K, Huang A, Nie J, Tan J, Xing S, Qu Y, et al. IL-35 regulates the function of immune cells in tumor microenvironment. Front Immunol. 2021;12:683332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tamama K, Funnell J, Cesarz Z. Bone morphogenic protein 2 is a key regulator of spheroidal aggregates of mesenchymal stem cells. FASEB J. 2016;30:695.692–695.692.

    Article  Google Scholar 

  34. Zou Z, Chang H, Li H, Wang S. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis. 2017;22:1321–35.

    Article  CAS  PubMed  Google Scholar 

  35. Raza MH, Siraj S, Arshad A, Waheed U, Aldakheel F, Alduraywish S, et al. ROS-modulated therapeutic approaches in cancer treatment. J Cancer Res Clin Oncol. 2017;143:1789–809.

    Article  CAS  PubMed  Google Scholar 

  36. Palma FR, He C, Danes JM, Paviani V, Coelho DR, Gantner BN, et al. Mitochondrial superoxide dismutase: what the established, the intriguing, and the novel reveal about a key cellular redox switch. Antioxid Redox Signal. 2020;32:701–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fan C, Chen J, Wang Y, Wong YS, Zhang Y, Zheng W, et al. Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway. Free Radic Biol Med. 2013;65:305–16.

    Article  CAS  PubMed  Google Scholar 

  38. Kim W, Lee S, Seo D, Kim D, Kim K, Kim E, et al. Cellular stress responses in radiotherapy. Cells. 2019;8:1105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mirlekar B. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: its implications in cancer immunotherapy. SAGE Open Med. 2022;10:20503121211069012.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. J Immunol. 2012;189:5590–601.

    Article  CAS  PubMed  Google Scholar 

  41. Xue W, Yan D, Kan Q. Interleukin-35 as an emerging player in tumor microenvironment. J Cancer. 2019;10:2074–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (grants 82072659, 82272680, 82272799, 82030092, 82271895, 82072752, 82072657, 82072716, 82173295, 82072691, 82272767, 82273362, 82103006, 82103222, 82273259, 82273284, 82203402, 82203019 and 82203169), Tianjin Science Foundation for Distinguished Young Scholars (grants 19JCJQJC63100), the National Key Research and Development Program of China(2021YFA1201100); by the NIH grant R01CA233844 (to Shengyu Yang), Tianjin Research Innovation Project for Postgraduate Students(2022BKY162, 2021YJSB262), Tianjin Key Medical Discipline(Specialty) Construction Project(TJYXZDXK-009A), Key Programs of Science Foundation of Heilongjiang Province (ZD2019H009).

Author information

Author notes

  1. These authors contributed equally: Huizhi Sun, Yi Ge, Jing Liu.

Authors and Affiliations

  1. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    Huizhi Sun, Yi Ge, Jing Liu, Zengxun Li, Hui Li, Tiansuo Zhao, Xiuchao Wang, Yukuan Feng, Hongwei Wang, Song Gao, Shengyu Yang, Antao Chang, Jihui Hao & Chongbiao Huang

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Lei Shi

  3. Department of Cellular and Molecular Physiology, the Pennsylvania State University College of Medicine, Hershey, PA, USA

    Shengyu Yang

  4. Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Peiqing Sun

Authors
  1. Huizhi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zengxun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tiansuo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiuchao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukuan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Song Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shengyu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peiqing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Antao Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jihui Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Chongbiao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JH and CH was responsible for designing and supervising the whole research. YG and HS was responsible for performing the experiments, analysing data and writing the manuscript. ZL, HL and JL conducted the data analyses. AC, HW and SG analysed and interpretated the experimental data. SY and PS contributed to revising the work. TZ, XW, YF, and SL provided supports on methodology and resources. All authors approved the final manuscript.

Corresponding authors

Correspondence to Antao Chang, Jihui Hao or Chongbiao Huang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, H., Ge, Y., Liu, J. et al. Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma. Oncogene 43, 776–788 (2024). https://doi.org/10.1038/s41388-024-02938-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-02938-0

Search

Advanced search

Quick links