Abstract：
:The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ+/TNFα+/IL10+ CD4+ and CD8+ T cells. Immunodepletion of CD4+ but not CD8+ T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway.Significance: This provocative study suggests that inhibiting complement activation may heighten immunotherapeutic responses in lung cancer, offering findings with immediate implications, given the existing clinical availability of complement antagonists. Cancer Res; 78(1); 143-56. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kwak JW,Laskowski J,Li HY,McSharry MV,Sippel TR,Bullock BL,Johnson AM,Poczobutt JM,Neuwelt AJ,Malkoski SP,Weiser-Evans MC,Lambris JD,Clambey ET,Thurman JM,Nemenoff RAdoi
10.1158/0008-5472.CAN-17-0240subject
Has Abstractpub_date
2018-01-01 00:00:00pages
143-156issue
1eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-0240journal_volume
78pub_type
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