Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer.
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.


CONCLUSIONS
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.
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Stephanie
S
Downs-Canner
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Deepa
D
Magge
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Roshni
R
Ravindranathan
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Mark E
ME
O'Malley
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Lily
L
Francis
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Zuqiang
Z
Liu
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Z
Z
Sheng Guo
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Natasa
N
Obermajer
Department of Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. bartdl@upmc.edu.
David L
DL
Bartlett
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000037:antagonists & inhibitors*; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D004546:Elapid Venoms / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005098:Exotoxins / Q000494:pharmacology; D005260:Female; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018089:Superantigens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
D003176:Complement C3; D051056:Complement Inactivating Agents; D004546:Elapid Venoms; D005098:Exotoxins; D012333:RNA, Messenger; D018089:Superantigens; C016310:cobra venom factor; C416085:staphylococcal exotoxin 1