Skip to main content
SpringerLink
Log in

Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Complement is a central part of both the innate and adaptive immune response and its activation has traditionally been considered part of the immunosurveillance response against cancer. Its pro-inflammatory role and its contribution to the development of many illnesses associated with inflammatory states implicate complement in carcinogenesis.

Methods

We evaluated the role of three protein inhibitors of complement—cobra venom factor, humanized cobra venom factor, and recombinant staphylococcus aureus superantigen-like protein 7—in the setting of a transplantable murine colon cancer model. Outcomes were evaluated by monitoring tumor growth, and flow cytometry, ELISPOT, and quantitative real-time PCR were used to determine the impact of complement inhibition on the host immune response.

Results

Complement inhibitors were effective at depleting complement component C3 in tumor bearing mice and this was temporally correlated with a decreased rate of tumor growth during the establishment of tumors. Treatment with cobra venom factor resulted in increased CD8+ T cells as a percentage of tumor-infiltrating cells as well as a reduced immunosuppressive environment evidenced by decreased myeloid derived suppressor cells in splenocytes of treated mice. Complement inhibition resulted in increased expression of the chemoattractive cytokines CCL5, CXCL10, and CXCL11.

Discussion

Complement depletion represents a promising mode of immunotherapy in cancer by its ability to impair tumor growth by increasing the host’s effective immune response to tumor and diminishing the immunosuppressive effect created by the tumor microenvironment and ultimately could be utilized as a component of combination immunotherapy.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343:227–35.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol. 2008;6:132–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Dechant M, Weisner W, Berger S, et al. Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies. Cancer Res. 2008;68:4998–5003.

    Article  PubMed  CAS  Google Scholar 

  4. Rutkowski MJ, Sughrue ME, Kane AJ, et al. Cancer and the complement cascade. Mol Cancer Res. 2010;8:1453–65.

    Article  PubMed  CAS  Google Scholar 

  5. Markiewski MM, Lambris JD. Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol. 2009;30:286–92.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Nitta H, Murakami Y, Wada Y, et al. Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness. Oncol Rep. 2014;32:1715–9.

    PubMed  CAS  Google Scholar 

  7. Yu J, Caragine T, Chen S, Morgan BP, Frey AB, Tomlinson S. Protection of human breast cancer cells from complement-mediated lysis by expression of heterologous CD59. Clin Exp Immunol. 1999;115:13–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs). Mol Immunol. 2003;40:109–23.

    Article  PubMed  CAS  Google Scholar 

  9. Kempshall E, Thebault S, Morgan BP, Harris CL, Gallimore A. Complement-induced protectin: an explanation for the limitations of cell-based tumour immunotherapies. Immunol Cell Biol. 2012;90:869–71.

    Article  PubMed  CAS  Google Scholar 

  10. Reiter Y, Ciobotariu A, Fishelson Z. Sublytic complement attack protects tumor-cells from lytic doses of antibody and complement. Eur J Immunol. 1992;22:1207–13.

    Article  PubMed  CAS  Google Scholar 

  11. Reiter Y, Ciobotariu A, Jones J, Morgan BP, Fishelson Z. Complement membrane attack complex, perforin, and bacterial exotoxins induce K562 cells calcium-dependent cross-protection from lysis. J Immunol. 1995;155:2203–10.

    PubMed  CAS  Google Scholar 

  12. Markiewski MM, DeAngelis RA, Benencia F, et al. Modulation of the antitumor immune response by complement. Nat Immunol. 2008;9:1225–35.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Lu Y, Hu XB. C5a stimulates the proliferation of breast cancer cells via Akt-dependent RGC-32 gene activation. Oncol Rep. 2014;32:2817–23.

    PubMed  CAS  Google Scholar 

  14. Niculescu F, Rus HG, Retegan M, Vlaicu R. Persistent complement activation on tumor cells in breast cancer. Am J Pathol. 1992;140:1039–43.

    PubMed  CAS  PubMed Central  Google Scholar 

  15. Corrales L, Ajona D, Rafail S, et al. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J Immunol. 2012;189:4674–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Lucas SD, Karlsson-Parra A, Nilsson B, et al. Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Hum Pathol. 1996;27:1329–35.

    Article  PubMed  CAS  Google Scholar 

  17. Ytting H, Jensenius JC, Christensen IJ, et al. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer. Scand J Gastroenterol. 2004;39:674–9.

    Article  PubMed  CAS  Google Scholar 

  18. Gunn L, Ding C, Liu M, et al. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J Immunol. 2012;189:2985–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Kempshall E, Thebault S, Morgan BP, et al. Complement-induced protection: an explanation for the limitations of cell-based tumour immunotherapies. Immunol Cell Biol. 2012;90:869–71.

    Article  PubMed  CAS  Google Scholar 

  20. Hsieh CC, Chou HS, Yang HR, et al. The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells. Blood. 2013;121:1760–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Song X, Krelin Y, Dvorkin T, et al. CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells. J Immunol. 2005;175:8200–8.

    Article  PubMed  CAS  Google Scholar 

  22. Bunt SK, Sinha P, Clements VK, et al. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol. 2006;176:284–90.

    Article  PubMed  CAS  Google Scholar 

  23. Obermajer N, Muthuswamy R, Lesnock J, et al. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118:5498–505.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Obermajer N, Muthuswamy R, Odunsi K, et al. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011;71:7463–70.

    Article  PubMed  CAS  Google Scholar 

  25. Vogel CW, Fritzinger DC. Cobra venom factor: structure, function, and humanization for therapeutic complement depletion. Toxicon. 2010;56:1198–222.

    Article  PubMed  CAS  Google Scholar 

  26. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004;350:552–9.

    Article  PubMed  CAS  Google Scholar 

  27. Magge D, Guo ZS, O’Malley ME, et al. Inhibitors of C5 complement enhance vaccinia virus oncolysis. Cancer Gene Ther. 2013;20:342–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Evgin L, Acuna SA, Tanese de Souza C, et al. Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques. Mol Ther. 2015;23:1066–76.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

Supported in part by U.S. National Institutes of Health (NIH) Grant R01CA155925 (to DLB) and by David C. Koch Regional Therapy Cancer Center. DM and SDC are supported by training grant T32CA113263 from the National Cancer Institute. This project used University of Pittsburgh Cancer Institute shared resources that are supported in part by NIH grant award P30CA047904. Special thanks to Dr. Stephen Thorne’s group at the University of Pittsburgh for providing MC38-luc cells, Dr. John Fraser’s group in Auckland, New Zealand, for their collaboration and for providing SSL7 protein for our study, and Dr. Carl Wilhelm Vogel for collaboration and providing hCVF for our study.

Disclosure

The authors declare no conflict of interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

      Stephanie Downs-Canner MD, Deepa Magge MD, Roshni Ravindranathan MS, Mark E. O’Malley BA, Lily Francis MBBS, MS, Zuqiang Liu PhD, Z. Sheng Guo PhD, Natasa Obermajer PhD & David L. Bartlett MD

    Authors
    1. Stephanie Downs-Canner MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Deepa Magge MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Roshni Ravindranathan MS
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Mark E. O’Malley BA
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Lily Francis MBBS, MS
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Zuqiang Liu PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Z. Sheng Guo PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Natasa Obermajer PhD
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. David L. Bartlett MD
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to David L. Bartlett MD.

    Additional information

    Stephanie Downs-Canner and Deepa Magge contributed equally to this article.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    10434_2015_4778_MOESM1_ESM.tif

    Protein complement inhibitors do not directly target MC38 cells in vitro. (a) Fluorescent microscopy pictures of MC38 luc cells incubated in DMEM/10 %FBS ± CVF, ± hCVF (c), ± SSL7 (e). (b) Viable cell assay following a 48 h incubation period of MC38 cells with or without CVF, ± hCVF (d), ± SSL7 (f). Supplementary material 1 (TIFF 331 kb)

    10434_2015_4778_MOESM2_ESM.tif

    Complement inhibition with CVF results in altered peripheral lymphoid composition. (a) FACS analysis results comparing the percentage of CD3 + CD8 + granzyme B + cells in the spleens of PBS-treated mice compared to CVF-treated mice demonstrate a higher percentage in PBS-treated mice (48.6 % vs 37.4 %; p value 0.001). (b) Splenocytes from PBS-treated and CVF-treated mice did not show a difference in IFNγ production after a 48-hour incubation with irradiated MC38 cells when evaluated by ELISPOT (3.2 spots/500,000 splenocytes vs 4.4 spots/500,000 splenocytes; p-value 0.3) 7 days after tumor establishment but at day 12 (c) PBS-treated mice demonstrated significantly more spots/500,000 splenocytes compared to CVF-treated mice (7.7 vs 4.4; p-value 0.037). Supplementary material 2 (TIFF 77 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Downs-Canner, S., Magge, D., Ravindranathan, R. et al. Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer. Ann Surg Oncol 23, 655–662 (2016). https://doi.org/10.1245/s10434-015-4778-7

    Download citation

    • Received:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1245/s10434-015-4778-7

    Keywords

    search

    Navigation