Skip to main content

Advertisement

SpringerLink
Log in

Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Vascular-targeted photodynamic therapy (VTP) takes advantage of intravascular excitation of a photosensitizer (PS) to produce cytotoxic reactive oxygen species (ROS). These ROS are potent mediators of vascular damage inducing rapid local thrombus formation, vascular occlusion, and tissue hypoxia. This light-controlled process is used for the eradication of solid tumors with Pd-bacteriochlorophyll derivatives (Bchl) as PS. Unlike classical photodynamic therapy (PDT), cancer cells are not the primary target for VTP but instead are destroyed by treatment-induced oxygen deprivation. VTP initiates acute local inflammation inside the illuminated area accompanied by massive tumor tissue death. Consequently, in the present study, we addressed the possibility of immune response induction by the treatment that may be considered as an integral part of the mechanism of VTP-mediated tumor eradication. The effect of VTP on the host immune system was investigated using WST11, which is now in phase II clinical trials for age-related macular degeneration and intended to be evaluated for cancer therapy. We found that a functional immune system is essential for successful VTP. Long-lasting systemic antitumor immunity was induced by VTP involving both cellular and humoral components. The antitumor effect was cross-protective against mismatched tumors, suggesting VTP-mediated production of overlapping tumor antigens, possibly from endothelial origin. Based on our findings we suggest that local VTP might be utilized in combination with other anticancer therapies (e.g., immunotherapy) for the enhancement of host antitumor immunity in the treatment of both local and disseminated disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Adam JK, Odhav B, Bhoola KD (2003) Immune responses in cancer. Pharmacol Ther 99:113–132

    Article  PubMed  CAS  Google Scholar 

  2. Agaiby AD, Dyson M (1999) Immuno-inflammatory cell dynamics during cutaneous wound healing. J Anat 195(Pt 4):531–542

    Article  PubMed  Google Scholar 

  3. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811

    Article  PubMed  CAS  Google Scholar 

  4. Boumedine RS, Roy DC (2005) Elimination of alloreactive T cells using photodynamic therapy. Cytotherapy 7:134–143

    Article  PubMed  CAS  Google Scholar 

  5. Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D, Wang HJ, Elashoff RM, McBride WH, Mukherji B, Cochran AJ, Glaspy JA, Economou JS (2003) Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res 9:998–1008

    PubMed  CAS  Google Scholar 

  6. Castano AP, Mroz P, Hamblin MR (2006) Photodynamic therapy and anti-tumour immunity. Nat Rev Cancer 6:535–545

    Article  PubMed  CAS  Google Scholar 

  7. Chen WR, Huang Z, Korbelik M, Nordquist RE, Liu H (2006) Photoimmunotherapy for cancer treatment. J Environ Pathol Toxicol Oncol 25:281–291

    PubMed  CAS  Google Scholar 

  8. Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283–289

    Article  PubMed  CAS  Google Scholar 

  9. Dolmans DE, Fukumura D, Jain RK (2003) Photodynamic therapy for cancer. Nat Rev Cancer 3:380–387

    Article  PubMed  CAS  Google Scholar 

  10. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q (1998) Photodynamic therapy. J Natl Cancer Inst 90:889–905

    Article  PubMed  CAS  Google Scholar 

  11. Elmets CA, Bowen KD (1986) Immunological suppression in mice treated with hematoporphyrin derivative photoradiation. Cancer Res 46:1608–1611

    PubMed  CAS  Google Scholar 

  12. Felicetti P, Mennecozzi M, Barucca A, Montgomery S, Orlandi F, Manova K, Houghton AN, Gregor PD, Concetti A, Venanzi FM (2007) Tumor endothelial marker 8 enhances tumor immunity in conjunction with immunization against differentiation Ag. Cytotherapy 9:23–34

    Article  CAS  Google Scholar 

  13. Gollnick SO, Owczarczak B, Maier P (2006) Photodynamic therapy and anti-tumor immunity. Laser Surg Med 38:509–515

    Article  Google Scholar 

  14. Gollnick SO, Vaughan L, Henderson BW (2002) Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 62:1604–1608

    PubMed  CAS  Google Scholar 

  15. Gross S, Gilead A, Scherz A, Neeman M, Salomon Y (2003) Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat Med 9:1327–1331

    Article  PubMed  CAS  Google Scholar 

  16. Habib Moinuddin S, Ali R (2006) Peroxinitrite modified DNA: a better antigen for systemic lupus erythematosus anti-DNA autoantibodies. Biotechnol Appl Biochem 43(Pt 2):65–70

    Article  Google Scholar 

  17. Henderson BW, Gollnick SO, Snyder JW, Busch TM, Kousis PC, Cheney RT, Morgan J (2004) Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors. Cancer Res 64:2120–2126

    Article  PubMed  CAS  Google Scholar 

  18. Houghton AN, Guevara-Patino JA (2004) Immune recognition of self in immunity against cancer. J Clin Invest 114:468–471

    PubMed  CAS  Google Scholar 

  19. Jalili A, Makowski M, Switaj T, Nowis D, Wilczynski GM, Wilczek E, Chorazy-Massalska M, Radzikowska A, Maslinski W, Bialy L, Sienko J, Sieron A, Adamek M, Basak G, Mroz P, Krasnodebski IW, Jakobisiak M, Golab J (2004) Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells. Clin Cancer Res 10:4498–4508

    Article  PubMed  CAS  Google Scholar 

  20. Jolles CJ, Ott MJ, Straight RC, Lynch DH (1988) Systemic immunosuppression induced by peritoneal photodynamic therapy. Am J Obstet Gynecol 158:1446–1453

    PubMed  CAS  Google Scholar 

  21. Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, Pamer EG, Littman DR, Lang RA (2002) In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17:211–220

    Article  PubMed  CAS  Google Scholar 

  22. Kasprzyk PG, Song SU, Di Fiore PP, King CR (1992) Therapy of an animal model of human gastric cancer using a combination of anti-erbB–2 monoclonal antibodies. Cancer Res 52:2771–2776

    PubMed  CAS  Google Scholar 

  23. Korbelik M (2006) PDT-associated host response and its role in the therapy outcome. Laser Surg Med 38:500–508

    Article  Google Scholar 

  24. Korbelik M, Cecic I (1999) Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett 137:91–98

    Article  PubMed  CAS  Google Scholar 

  25. Korbelik M, Dougherty GJ (1999) Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res 59:1941–1946

    PubMed  CAS  Google Scholar 

  26. Korbelik M, Sun J, Cecic I (2005) Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer Res 65:1018–1026

    PubMed  CAS  Google Scholar 

  27. Koudinova NV, Pinthus JH, Brandis A, Brenner O, Bendel P, Ramon J, Eshhar Z, Scherz A, Salomon Y (2003) Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts. Int J Cancer 104:782–789

    Article  PubMed  CAS  Google Scholar 

  28. Kousis PC, Henderson BW, Maier PG, Gollnick SO (2007) Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils. Cancer Res 67:10501–10510

    Article  PubMed  CAS  Google Scholar 

  29. Lynch DH, Haddad S, King VJ, Ott MJ, Straight RC, Jolles CJ (1989) Systemic immunosuppression induced by photodynamic therapy (PDT) is adoptively transferred by macrophages. Photochem Photobiol 49:453–458

    Article  PubMed  CAS  Google Scholar 

  30. Macdonald IJ, Dougherty GJ (2001) Basic principles of photodynamic therapy. J Porphyrins Phthalocyanines 5:105–129

    Article  CAS  Google Scholar 

  31. Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A (2005) WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol 81:342–351

    Article  PubMed  CAS  Google Scholar 

  32. Musser DA, Fiel RJ (1991) Cutaneous photosensitizing and immunosuppressive effects of a series of tumor localizing porphyrins. Photochem Photobiol 53:119–123

    Article  PubMed  CAS  Google Scholar 

  33. Nowis D (2005) The influence of photodynamic therapy on the immune response. Photodiagn Photodyn Ther 2:283–298

    Article  CAS  Google Scholar 

  34. Ohmori H, Kanayama N (2005) Immunogenicity of an inflammation-associated product, tyrosine nitrated self-proteins. Autoimmun Rev 4:224–229

    Article  PubMed  CAS  Google Scholar 

  35. Ohmori H, Oka M, Nishikawa Y, Shigemitsu H, Takeuchi M, Magari M, Kanayama N (2005) Immunogenicity of autologous IgG bearing the inflammation-associated marker 3-nitrotyrosine. Immunol Lett 96:47–54

    Article  PubMed  CAS  Google Scholar 

  36. Preise D, Mazor O, Koudinova N, Liscovitch M, Scherz A, Salomon Y (2003) Bypass of tumor drug resistance by antivascular therapy. Neoplasia 5:475–480

    PubMed  CAS  Google Scholar 

  37. Ribas A, Timmerman JM, Butterfield LH, Economou JS (2003) Determinant spreading and tumor responses after peptide-based cancer immunotherapy. Trends Immunol 24:58–61

    Article  PubMed  CAS  Google Scholar 

  38. Rodeberg DA, Erskine C, Celis E (2007) In vitro induction of immune responses to shared tumor-associated antigens in rhabdomyosarcoma. J Pediatr Surg 42:1396–1402

    Article  PubMed  Google Scholar 

  39. Saji H, Song W, Furumoto K, Kato H, Engleman EG (2006) Systemic antitumor effect of intratumoral injection of dendritic cells in combination with local photodynamic therapy. Clin Cancer Res 12:2568–2574

    Article  PubMed  CAS  Google Scholar 

  40. Sapoznikov A, Fischer JA, Zaft T, Krauthgamer R, Dzionek A, Jung S (2007) Organ-dependent in vivo priming of naive CD4+, but not CD8+, T cells by plasmacytoid dendritic cells. J Exp Med 204:1923–1933

    Article  PubMed  CAS  Google Scholar 

  41. Schreiber GJ, Hellstrom KE, Hellstrom I (1992) An unmodified anticarcinoma antibody, BR96, localizes to and inhibits the outgrowth of human tumors in nude mice. Cancer Res 52:3262–3266

    PubMed  CAS  Google Scholar 

  42. Sondel PM, Hank JA (2001) Antibody-directed, effector cell-mediated tumor destruction. Hematol Oncol Clin North Am 15:703–721

    Article  PubMed  CAS  Google Scholar 

  43. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Article  PubMed  CAS  Google Scholar 

  44. Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo M, Soo KC (2007) Photodynamic-therapy-activated immune response against distant untreated tumours in recurrent angiosarcoma. Lancet Oncol 8:950–952

    Article  PubMed  CAS  Google Scholar 

  45. Valamanesh F, Berdugo M, Bejjani RA, Savoldelli M, Jeanny JC, Brun PH, Blanc D, Ben-Ezra D, Behar-Cohen F (2004) Reduced collateral effect of photodynamic therapy (PDT) using a new water soluble photosensitizing agent. Invesr Ophthalmol Vis Sci 45:

  46. van Beijnum JR, Dings RP, van der Linden E, Zwaans BM, Ramaekers FC, Mayo KH, Griffioen AW (2006) Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 108:2339–2348

    Article  PubMed  Google Scholar 

  47. van Duijnhoven FH, Tollenaar RA, Terpstra OT, Kuppen PJ (2005) Locoregional therapies of liver metastases in a rat CC531 coloncarcinoma model results in increased resistance to tumour rechallenge. Clin Exp Metastasis 22:247–253

    Article  PubMed  Google Scholar 

  48. Wuttge DM, Bruzelius M, Stemme S (1999) T-cell recognition of lipid peroxidation products breaks tolerance to self proteins. Immunology 98:273–279

    Article  PubMed  CAS  Google Scholar 

  49. Yla-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL (1994) Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb 14:32–40

    PubMed  CAS  Google Scholar 

  50. Yusuf N, Katiyar SK, Elmets CA (2008) The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4(+) and CD8(+) T cells and can be adoptively transferred to naive recipients. Photochem Photobiol 84:366–370

    Article  PubMed  CAS  Google Scholar 

  51. Zilberstein J, Schreiber S, Bloemers MC, Bendel P, Neeman M, Schechtman E, Kohen F, Scherz A, Salomon Y (2001) Antivascular treatment of solid melanoma tumors with bacteriochlorophyll-serine-based photodynamic therapy. Photochem Photobiol 73:257–266

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Prof. L. Eisenbach and Dr. E. Tzehoval for valuable discussions and technical help, to Dr. Ori Brener for histopathology work, to Ester Shai, for her technical help. Study supported by STEBA-BIOTECH (France).

Author information

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel

    Dina Preise, Roni Oren, Itai Glinert & Yoram Salomon

  2. Department of Plant Science, The Weizmann Institute of Science, Rehovot, Israel

    Avigdor Scherz

  3. Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel

    Steffen Jung

  4. Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel

    Vyacheslav Kalchenko

Authors
  1. Dina Preise
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roni Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Itai Glinert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vyacheslav Kalchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steffen Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avigdor Scherz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoram Salomon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoram Salomon.

Additional information

Y.S. and A.S are the incumbents of the Tillie and Charles Lubin Professorial Chair in Biochemical Endocrinology, and the Robert and Yaddele Sklare Professorial Chair in Biochemistry, respectively. S.J. is the incumbent of the Pauline Recanati Career Development Chair. D.P. in partial fulfillment of her PhD Thesis requirements at the Feinberg graduate school of the Weizmann Institute of Science.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Preise, D., Oren, R., Glinert, I. et al. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol Immunother 58, 71–84 (2009). https://doi.org/10.1007/s00262-008-0527-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0527-0

Keywords

Search

Navigation