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Immuno-therapeutic potential of Schistosoma mansoni and Trichinella spiralis antigens in a murine model of colon cancer

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Summary

Considerable evidence indicates a negative correlation between the prevalence of some parasitic infections and cancer and their interference with tumor growth. Therefore, parasitic antigens seem to be promising candidates for cancer immunotherapy. In this study, the therapeutic efficacy of autoclaved Schistosoma mansoni and Trichinella spiralis antigens against a colon cancer murine model was investigated. Both antigens showed immunomodulatory potential, as evidenced by a significant decrease in serum IL-17, a significant increase in serum IL-10, and the percentage of splenic CD4+T-cells and intestinal FoxP3+ Treg cells. However, treatment with S. mansoni antigen yielded protection against the deleterious effect of DMH-induced colon carcinogenesis only, with a significant decrease in the average lesion size and number of neoplasias per mouse. For the first time, we report an inhibitory effect of S. mansoni antigen on the progression of chemically induced colon carcinogenesis, but the exact mechanism has yet to be clarified. This anti-tumor strategy could introduce a new era of medicine in which a generation of anticancer vaccines of parasitic origin would boost the therapy for incurable cancers.

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Abbreviations

ASMA:

Autoclaved Schistosoma mansoni antigen

ATSA:

Autoclaved Trichinella spiralis antigen

DMH:

1,2-dimethylhydrazine

FoxP3 + Treg cells:

Forkhead box positive T regulatory cells

CIS:

Carcinoma in situ

TGF-β:

Transforming growth factor-beta

References

  1. Finn JO (2003) Cancer vaccines: between the idea and the reality. Nat Rev Immunol 3:630–641

    Article  CAS  PubMed  Google Scholar 

  2. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Darani HY, Yousefi M (2012) Parasites and cancers: parasite antigens as possible targets for cancer immunotherapy. Future Oncol 8(12):1529–1535

    Article  CAS  PubMed  Google Scholar 

  4. Akgül H, Tez M, Ünal AE, Keşkek M, Sayek I, Özçelik T (2003) Echinococcus against cancer: why not? Cancer 198(9):1999–2000. https://doi.org/10.1002/cncr.11752

    Article  Google Scholar 

  5. Chen L, He Z, Qin L, Li Q, Shi X, Zhao S, et al (2011) Antitumor effect of malaria parasite in a murine lewis lung cancer model through induction of innate and adaptive immunity. PLoS ONE 6(9), Article ID e24407

  6. Kang Y, Jo J, Cho M, Yu H, Leem S, Song KS et al (2013) Trichinella spiralis infection reduces tumor growth and metastasis of B16-F10 melanoma cells. Vet Parasitol 196:106–113

    Article  CAS  PubMed  Google Scholar 

  7. Zou J, Huang XX, Yin GW, Ding Y, Liu XY, Wang H, Chen QJ, Suo X (2011) Evaluation of Toxoplasma gondii as a live vaccine vector in susceptible and resistant hosts. Parasit Vectors 4:168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ubillos L, Freire T, Berriel E, Chiribao ML, Chiale C, Festari MF, Medeiros A, Mazal D, Rondán M, Bollati-Fogolín M, Rabinovich GA, Robello C, Osinaga E (2016) Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers. Int J Cancer 138:1719–1731

    Article  CAS  PubMed  Google Scholar 

  9. Eissa MM, Allam SR, El-Mahdi AR, El-Azzouni MZ (2000) Autoclaved cercarial vaccine against schistosomiasis: ultrastructural and biochemical analysis. Southeast Asian J Trop Med Public Health 31(1):8–15 11414466

    PubMed  Google Scholar 

  10. Eissa MM, El-Azzouni MZ, Mady RF, Fathy FM, Baddour NM (2012) Initial characterization of an autoclaved toxoplasma vaccine in mice. Exp Parasitol 131:310–316. https://doi.org/10.1016/j.exppara.2012.05.001

    Article  CAS  PubMed  Google Scholar 

  11. Eissa MM, Allam SR, El-Azzouni MZ, Maged HR, Dessouky IS (2003) Further studies on autoclaved cercarial vaccine against schistosomiasis safety, longevity and stability. J Egypt Soc Parasitol 33:541–560

    PubMed  Google Scholar 

  12. Hakomori S (2003) Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. Adv Exp Med Biol 491:369–402

    Article  Google Scholar 

  13. Baldus SE, Engelmann K, Hanisch FG (2004) MUC1 and the MUCs: a family of human mucins with impact in cancer biology. Crit Rev Clin Lab Sci 41(2):189–231

    Article  CAS  PubMed  Google Scholar 

  14. Eissa MM, El-Azzouni MZ, Bolous LM (2003) Vaccination trial against experimental trichinosis using autoclaved Trichinella spiralis larva vaccine. J Egypt Soc Parasitol 33:219–228

    PubMed  Google Scholar 

  15. Yang X, Yang Y, Wang Y, Zhan B, Gu Y, Cheng Y, Zhu X (2014) Excretory/secretory products from Trichinella spiralis adult worms ameliorate DSS-induced colitis in mice. PLoS One 9(5):e96454. https://doi.org/10.1371/journal.pone.0096454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pellegrino J, Katz N (1968) Experimental chemotherapy of schistosomiasis mansoni. Adv Parasitol 6:233–290

    Article  CAS  PubMed  Google Scholar 

  17. Pica-Mattoccia L, Cioli D (2004) Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. Int J Parasitol 34:27–533

    Article  CAS  Google Scholar 

  18. Wasson DL, Dougherky DA, Dick TA (1988) T. Spiralis induced by different Trichinella isolates. J Parasitol 74(2):283–287

    Article  Google Scholar 

  19. El-Aswad BW, Doenhoff MJ, El Hadidi AS, Schwaeble WJ, Lynch NJ (2011) Use of recombinant calreticulin and cercarial transformation fluid (CTF) in the serodiagnosis of Schistosoma mansoni. Immunobiology 216(3):379–385. https://doi.org/10.1016/j.imbio.2010.06.014

  20. Eissa MM, Mostafa DK, Ghazy AA, El-azzouni MZ, Boulos LM, Younis LK (2016) Anti- arthritic activity of Schistosoma mansoni and Trichinella Spiralis derived-antigens in adjuvant arthritis in rats: role of FOXP3+ Treg cells. PLoS One 11(11):e0165916. https://doi.org/10.1371/journal.pone.0165916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lowry OH, Rosebrough NS, Fan AL, Randall RS (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  22. Thurnherr N, Deschner EE, Stonehill EH, Lipkin M (1973) Induction of adenocarcinomas of the Colon in mice by weekly injections of 1,2-Dimethylhydrazine. Cancer Res 33:940–945

    CAS  PubMed  Google Scholar 

  23. Darani HY, Curtis RH, McNeice C, Price HP, Sayers JR, Doenhoff MJ (1997) Schistosoma mansoni: anomalous immunogenic properties of a 27 kDa larval serine protease associated with protective immunity. Parasitology 115(3):237–247

    Article  CAS  PubMed  Google Scholar 

  24. Wang XL, Fu BQ, Yang SJ, Wu XP, Cui GZ, Liu MF, Zhao Y, Yu YL, Liu XY, Deng HK, Chen QJ, Liu MY (2009) Trichinella spiralis-A potential anti-tumor agent. Vet Parasitol 159:249–252

    Article  CAS  PubMed  Google Scholar 

  25. Piatier-Tonneau D (2002) CD Guide: CD4. In Mason D, Andre P, Bensussan A, Buckley C, Civin C & Clark E, et al. (Eds) Leucocyte typing VII. White cell differentiation antigens. Proceedings of the 7th International Workshop and Conference. Harrogate, United Kingdom, 19–23 June 2002; New York, Oxford University Press

  26. Alberici P (2007) The adenoma-carcinoma sequence in colorectal Cancer: scratching the surface. PrintPartners Ipskamp, Enschede, The Netherlands Library of the University of Oregon

  27. Deane NG, Parker MA, Aramandla R, Diehl L, Lee WJ, Washington MK, Nanney LB, Shyr Y, Beauchamp RD (2001) Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice. Cancer Res 61:5389–5395

    CAS  PubMed  Google Scholar 

  28. Kim M, Grimmig T, Grimm M, Lazariotou M, Meier E, Rosenwald A, Tsaur I, Blaheta R, Heemann U, Germer CT, Waaga-Gasser AM, Gasser M (2013) Expression of Foxp3 in colorectal Cancer but not in Treg cells correlates with disease progression in patients with colorectal Cancer. PLoS One 8(1):e53630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gönner U, Wilsberg V, Junginger T, Berger MR, Galle PR, Moehler M (2005) Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behaviour of human colorectal cancer. Clin Cancer Res 11:1743–1750

    Article  CAS  PubMed  Google Scholar 

  30. Mougiakakos D (2011) Regulatory T cells in colorectal cancer: from biology to prognostic relevance. Cancers (Basel) 3(2):1708–1731. https://doi.org/10.3390/cancers3021708

    Article  CAS  Google Scholar 

  31. Salim OE, Hamid HK, Mekki SO, Suleiman SH, Ibrahim SZ (2010) Colorectal carcinoma associated with schistosomiasis: a possible causal relationship. World J Surg Oncol 8:68. https://doi.org/10.1186/1477-7819-8-68

    Article  Google Scholar 

  32. Matisz CE, McDougall JJ, Sharkey KA, McKay DM (2011) Helminth parasites and the modulation of joint inflammation. J Parasitol Res 942616

  33. Ladoire S, Martin F, Ghiringhelli F (2011) Prognostic role of FOXP3+ regulatory T-cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60:909–918

    Article  CAS  PubMed  Google Scholar 

  34. Ondondo B, Jones E, Godkin A, Gallimore A (2013) Home sweet home: the tumor microenvironment as a haven for regulatory T cells. Front Immunol 4(197)

  35. Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, Leusink M, Cheever AW, Shevach EM, Wynn TA (2004) The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol 172:3157–3166

    Article  CAS  PubMed  Google Scholar 

  36. Marinho FV, Alves CC, de Souza SC, da Silva CM, Cassali GD, Oliveira SC et al (2016) Schistosoma mansoni tegument (Smteg) induces IL-10 and modulates experimental airway inflammation. PLoS One 11(7):e0160118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Amedei A, Niccolai E, Benagiano M, Della Bella C, Cianchi F, Bechi P, Taddei A, Bencini L, Farsi M, Cappello P, Prisco D, Novelli F, D’Elios MM (2013) Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. Cancer Immunol Immunother 62:1249–1260

    Article  CAS  PubMed  Google Scholar 

  38. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R et al (2006) Cd4+ cd25+ foxp3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 1:e129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S (2010) Tumor-infiltrating t-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222:350–366

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J (2013) Interleukin-17: a promoter in colorectal Cancer progression. Clin Dev Immunol 2013:436307. https://doi.org/10.1155/2013/436307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Urban JF, Katona IM, Paul WE, Finkelman FD (1991) Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc Natl Acad Sci U S A 88(13):5513–5517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu Y, Pasche B (2007) TGF-β signalling alterations and susceptibility to colorectal cancer. Hum Mol Genet 16(SPEC):R14–R20. https://doi.org/10.1093/hmg/ddl486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favourable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102:18538–18543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Berriel E, Hill M, Barcia JJ, Ubillos L, Gonza’lez M, Detjen G et al (2005) Simple mucin-type cancer associated antigens are pre-cancerous biomarkers during 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Oncol Rep 14:219–228

    CAS  PubMed  Google Scholar 

  45. Brockhausen I (2006) Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Rep 7:599–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Thors C, Jansson B, Helin H, Linder E (2006) Thomsen-Friedenreich oncofetal antigen in Schistosoma mansoni: localization and immunogenicity in experimental mouse infection. Parasitology 132:73–81

    Article  CAS  PubMed  Google Scholar 

  47. Wolf DA, Wang S, Panzica MA, Bassily NH, Thompson NL (1996) Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to Schistosoma mansoni amino acid permease and Caenorhabditis elegans gene products. Cancer Res 56:5012–5022

    CAS  PubMed  Google Scholar 

  48. Ortega-Pierres MG, Yepez-Mulia L, Homan W, Gamble HR, Lim PL, Takahashi Y et al (1996) Workshop on a detailed characterization of Trichinella spiralis antigens: a platform for future studies on antigens and antibodies to this parasite. Parasite Immunol 18(6):273–284

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to Mrs. Dawlat Ahmed for technical assistance with animal experimentation.

Funding

This research did not receive any specific grant from funding agencies in public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Maha M. Eissa & Mervat Z. El-Azzouni

  2. Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Cherine A. Ismail

  3. Medical Microbiology and Immunology, Faculty of Medicine, Kafr-Elsheikh University, Kafr-Elsheikh, Egypt

    Amany A. Ghazy

  4. Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Mona A. Hadi

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  1. Maha M. Eissa
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  2. Cherine A. Ismail
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Correspondence to Cherine A. Ismail.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures and animal treatments were in compliance with the ARRIVE guidelines for care and use of laboratory animals and were approved by the Ethics Committee of the Faculty of Medicine, Alexandria University.

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Eissa, M.M., Ismail, C.A., El-Azzouni, M.Z. et al. Immuno-therapeutic potential of Schistosoma mansoni and Trichinella spiralis antigens in a murine model of colon cancer. Invest New Drugs 37, 47–56 (2019). https://doi.org/10.1007/s10637-018-0609-6

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