Opposing roles for complement component C5a in tumor progression and the tumor microenvironment.
Promoting complement (C) activation may enhance immunological mechanisms of anti-tumor Abs for tumor destruction. However, C activation components, such as C5a, trigger inflammation, which can promote tumor growth. We addressed the role of C5a on tumor growth by transfecting both human carcinoma and murine lymphoma with mouse C5a. In vitro growth kinetics of C5a, control vector, or parental cells revealed no significant differences. Tumor-bearing mice with C5a-transfected xenografted tumor cells had significantly less tumor burden as compared with control vector tumors. NK cells and macrophages infiltrated C5a-expressing tumors with significantly greater frequency, whereas vascular endothelial growth factor, arginase, and TNF-α production were significantly less. Tumor-bearing mice with high C5a-producing syngeneic lymphoma cells had significantly accelerated tumor progression with more Gr-1+CD11b+ myeloid cells in the spleen and overall decreased CD4+ and CD8+ T cells in the tumor, tumor-draining lymph nodes, and the spleen. In contrast, tumor-bearing mice with low C5a-producing lymphoma cells had a significantly reduced tumor burden with increased IFN-γ-producing CD4+ and CD8+ T cells in the spleen and tumor-draining lymph nodes. These studies suggest concentration of local C5a within the tumor microenvironment is critical in determining its role in tumor progression.
Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Lacey
L
Gunn
Chuanlin
C
Ding
Min
M
Liu
Yunfeng
Y
Ma
Chunjian
C
Qi
Yihua
Y
Cai
Xiaoling
X
Hu
Deep
D
Aggarwal
Huang-Ge
HG
Zhang
Jun
J
Yan
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
D015936:Complement C5a