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A Listeria-based vaccine targeting ISG15 exerts anti-tumor efficacy in renal cell carcinoma

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Abstract

Renal cell carcinoma (RCC) is the deadliest form of urological cancer and is projected to be the fourth most common neoplasm in the USA in males by 2040. In addition to the current poor prognosis with 5-year survival rates hardly reaching 15%, the prevalence of resistance to currently available systemic therapies has also established an urgent need to develop new treatment regimen(s) for advanced RCC. Interferon-stimulated gene 15 (ISG15) is the first identified ubiquitin-like modifier and has been intensively studied for its central role in innate immunity against intracellular pathogens. However, in this study, we identified ISG15 as a novel tumor-associated antigen and prognostic marker in RCC. Further, we therapeutically targeted elevated ISG15 expression by means of a Listeria monocytogenes (Lm)-based vaccine, designated Lm-LLO-ISG15, in both subcutaneous and orthotopic RCC mouse models. Treatment with Lm-LLO-ISG15 resulted in an influx of tumor-infiltrating effector T cells and significant anti-tumor efficacy in both subcutaneous and orthotopic RCC tumor models. Treatment with Lm-LLO-ISG15 also generated a robust interferon-gamma response and attracted a larger pool of polyfunctional T cells into the tumor microenvironment. Importantly, the therapeutic efficacy of Lm-LLO-ISG15 in RCC is comparable to that of anti-PD-1 and sunitinib, the current frontline therapies for RCC patients. Collectively, our work illustrates that targeting ISG15 in RCC with a CTL-based immunotherapy such as Lm-LLO-ISG15 is a promising and potentially translatable therapeutic strategy to enhance survival in RCC patients.

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Data availability

All data generated or analyzed during this study are included in the article and its supplementary information files. Data are available on request from the authors and where no data are available, if appropriate.

References

  1. Rahib L, Wehner MR, Matrisian LM, Nead KT (2021) Estimated projection of US Cancer incidence and death to 2040. JAMA Netw Open 4:e214708

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wei H, Miao J, Cui J, Zheng W, Chen X, Zhang Q, Liu F, Mao Z, Qiu S, Zhang D (2021) The prognosis and clinicopathological features of different distant metastases patterns in renal cell carcinoma: analysis based on the SEER database. Sci Rep 11:17822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Grünwald V, Eberhardt B, Bex A, Flörcken A, Gauler T, Derlin T, Panzica M, Dürr HR, Grötz KA, Giles RH et al (2018) An interdisciplinary consensus on the management of bone metastases from renal cell carcinoma. Nat Rev Urol 15:511–521

    Article  PubMed  PubMed Central  Google Scholar 

  4. Perng Y-C, Lenschow DJ (2018) ISG15 in antiviral immunity and beyond. Nat Rev Microbiol 16:423–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang M, Li J, Yan H, Huang J, Wang F, Liu T, Zeng L, Zhou F (2021) ISGylation in innate antiviral immunity and pathogen defense responses: a review. Front Cell Dev Biol 9:3196

    Google Scholar 

  6. Budhwani M, Mazzieri R, Dolcetti R (2018) Plasticity of type I interferon-mediated responses in cancer therapy: from anti-tumor immunity to resistance. Front Oncol 8:322

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chen R-H, Xiao Z-W, Yan X-Q, Han P, Liang F-Y, Wang J-Y, Yu S-T, Zhang T-Z, Chen S-Q, Zhong Q et al (2020) Tumor cell-secreted ISG15 promotes tumor cell migration and immune suppression by inducing the macrophage M2-like phenotype. Front Immunol 11:594775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bolado-Carrancio A, Lee M, Ewing A, Muir M, Macleod KG, Gallagher WM, Nguyen LK, Carragher NO, Semple CA, Brunton VG et al (2021) ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling. Oncogene 40:6235–6247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alcalá S, Sancho P, Martinelli P, Navarro D, Pedrero C, Martín-Hijano L, Valle S, Earl J, Rodríguez-Serrano M, Ruiz-Cañas L et al (2020) ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity. Nat Commun 11:2682

    Article  PubMed  PubMed Central  Google Scholar 

  10. Desai SD, Reed RE, Burks J, Wood LM, Pullikuth AK, Haas AL, Liu LF, Breslin JW, Meiners S, Sankar S (2012) ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells. Exp Biol Med (Maywood) 237:38–49

    Article  CAS  PubMed  Google Scholar 

  11. Kariri YA, Alsaleem M, Joseph C, Alsaeed S, Aljohani A, Shiino S, Mohammed OJ, Toss MS, Green AR, Rakha EA (2021) The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer. Breast Cancer Res Treat 185:293–305

    Article  CAS  PubMed  Google Scholar 

  12. Chen RH, Du Y, Han P, Wang HB, Liang FY, Feng GK, Zhou AJ, Cai MY, Zhong Q, Zeng MS et al (2016) ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma. Oncotarget 7:16910–16922

    Article  PubMed  PubMed Central  Google Scholar 

  13. Qu T, Zhang W, Qi L, Cao L, Liu C, Huang Q, Li G, Li L, Wang Y, Guo Q et al (2020) ISG15 induces ESRP1 to inhibit lung adenocarcinoma progression. Cell Death Dis 11:511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hochnadel I, Hoenicke L, Petriv N, Neubert L, Reinhard E, Hirsch T, Alfonso JCL, Suo H, Longerich T, Geffers R et al (2022) Safety and efficacy of prophylactic and therapeutic vaccine based on live-attenuated Listeria monocytogenes in hepatobiliary cancers. Oncogene 41:2039–2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wood LM, Pan ZK, Seavey MM, Muthukumaran G, Paterson Y (2012) The ubiquitin-like protein, ISG15, is a novel tumor-associated antigen for cancer immunotherapy. Cancer Immunol Immunother 61:689–700

    Article  CAS  PubMed  Google Scholar 

  16. Oladejo M, Paterson Y, Wood LM (2021) Clinical experience and recent advances in the development of Listeria-based tumor immunotherapies. Front Immunol 12:642316–642316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oladejo M, Nguyen H-M, Silwal A, Reese B, Paulishak W, Markiewski MM, Wood LM (2022) Listeria-based immunotherapy directed against CD105 exerts anti-angiogenic and anti-tumor efficacy in renal cell carcinoma. Front Immunol. https://doi.org/10.3389/fimmu.2022.1038807

    Article  PubMed  PubMed Central  Google Scholar 

  18. Oladejo M, Wood L (2022) 1180 Listeria-based immunotherapy sculpts CD8+T cell response in the tumor microenvironment to control renal cell carcinoma. J Immunother Cancer 10(Suppl 2):A1–A1595

    Google Scholar 

  19. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, Varambally S (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19:649–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murphy KA, James BR, Wilber A, Griffith TS (2017) A syngeneic mouse model of metastatic renal cell carcinoma for quantitative and longitudinal assessment of preclinical therapies. J Vis Exp 122:e55080

    Google Scholar 

  21. Ghouse SM, Nguyen H-M, Bommareddy PK, Guz-Montgomery K, Saha D (2020) Oncolytic herpes simplex virus encoding IL12 controls triple-negative breast cancer growth and metastasis. Front Oncol 10:384

    Article  PubMed  PubMed Central  Google Scholar 

  22. Brannon AR, Reddy A, Seiler M, Arreola A, Moore DT, Pruthi RS, Wallen EM, Nielsen ME, Liu H, Nathanson KL et al (2010) Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer 1:152–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jiménez Fernández D, Hess S, Knobeloch K-P (2020) Strategies to target ISG15 and USP18 toward therapeutic applications. Front Chem 7:923

    Article  PubMed  PubMed Central  Google Scholar 

  24. Devaud C, Westwood JA, John LB, Flynn JK, Paquet-Fifield S, Duong CP, Yong CS, Pegram HJ, Stacker SA, Achen MG et al (2014) Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. Mol Ther 22:18–27

    Article  CAS  PubMed  Google Scholar 

  25. Zhang W, Fan W, Rachagani S, Zhou Z, Lele SM, Batra SK, Garrison JC (2019) Comparative study of subcutaneous and orthotopic mouse models of prostate cancer: vascular perfusion, vasculature density, hypoxic burden and BB2r-targeting efficacy. Sci Rep 9:11117

    Article  PubMed  PubMed Central  Google Scholar 

  26. Angulo JC, Shapiro O (2019) The changing therapeutic landscape of metastatic renal cancer. Cancers (Basel) 11:1227

    Article  CAS  PubMed  Google Scholar 

  27. Wan B, Liu B, Huang Y, Yu G, Lv C (2019) Prognostic value of immune-related genes in clear cell renal cell carcinoma. Aging (Albany NY) 11:11474–11489

    Article  CAS  PubMed  Google Scholar 

  28. Jia YY, Tan WJ, Duan FF, Pan ZM, Chen X, Yin YL, Jiao XA (2017) A genetically modified attenuated listeria vaccine expressing HPV16 E7 kill tumor cells in direct and antigen-specific manner. Front Cell Infect Microbiol 7:279

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kim SH, Castro F, Paterson Y, Gravekamp C (2009) High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action. Cancer Res 69:5860–5866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tenold M, Ravi P, Kumar M, Bowman A, Hammers H, Choueiri TK Jr (2020) PNL: current approaches to the treatment of advanced or metastatic renal cell carcinoma. American Society of Clinical Oncology Educational Book, pp 187–196

  31. Xu G, Feng D, Yao Y, Li P, Sun H, Yang H, Li C, Jiang R, Sun B, Chen Y (2020) Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization. Oncogene 39:1429–1444

    Article  CAS  PubMed  Google Scholar 

  32. Hochnadel I, Hoenicke L, Petriv N, Neubert L, Reinhard E, Hirsch T, Alfonso JCL, Suo H, Longerich T, Geffers R et al (2022) Correction: Safety and efficacy of prophylactic and therapeutic vaccine based on live-attenuated Listeria monocytogenes in hepatobiliary cancers. Oncogene 41:2787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim VM, Blair AB, Lauer P, Foley K, Che X, Soares K, Xia T, Muth ST, Kleponis J, Armstrong TD et al (2019) Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies. J Immunother Cancer 7:132

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mkrtichyan M, Chong N, Abu Eid R, Wallecha A, Singh R, Rothman J, Khleif SN (2013) Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy. J Immunother Cancer 1:15

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nguyen HM, Bommareddy PK, Silk AW, Saha D (2021) Optimal timing of PD-1 blockade in combination with oncolytic virus therapy. Semin Cancer Biol 86:971–980

    Article  PubMed  Google Scholar 

  36. Serra-Bellver P, Valpione S, Lorigan P (2016) Sequential immunotherapy regimens-expect the unexpected. Lancet Oncol 17:854–855

    Article  PubMed  Google Scholar 

  37. Wilson T, Taylor H, Winter H, Herbert C (2021) Sequential immunotherapy in melanoma: is it a realistic alternative to dual immunotherapy? Melanoma Res 31:366–370

    CAS  PubMed  Google Scholar 

  38. Rizzo M, Porta C (2017) Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence. Ther Adv Urol 9:195–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Shreyas Gaikwad for his technical support in the Western Blot experiments.

Funding

LW is supported by a grant from NIH (1R15CA216205-01).

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Authors and Affiliations

  1. Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA

    Hong-My Nguyen, Mariam Oladejo, Wyatt Paulishak & Laurence M. Wood

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  1. Hong-My Nguyen
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  2. Mariam Oladejo
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  3. Wyatt Paulishak
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  4. Laurence M. Wood
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Contributions

HMN and LMW contributed to the study’s conception and design. HMN carried out experiments, data collection and analysis, preparation of figures, and manuscript writing. MO assisted in the orthotopic study and reviewed the manuscript. WP assisted in vitro studies and reviewed the manuscript. LMW conceptualized the study, acquired funding, provided supervision, and reviewed and approved the final manuscript.

Corresponding author

Correspondence to Laurence M. Wood.

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The authors declare that they have no financial interests.

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All applicable international, national, and institutional standards for the care and use of experimental animals were followed. All studies involving animals were carried out by the ethical standards of the Texas Tech University Health Sciences Center.

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Nguyen, HM., Oladejo, M., Paulishak, W. et al. A Listeria-based vaccine targeting ISG15 exerts anti-tumor efficacy in renal cell carcinoma. Cancer Immunol Immunother 72, 2889–2903 (2023). https://doi.org/10.1007/s00262-022-03352-9

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  • DOI: https://doi.org/10.1007/s00262-022-03352-9

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