Complement Activation via a C3a Receptor Pathway Alters CD4 + T Lymphocytes and Mediates Lung Cancer Progression.

Autor:	Kwak JW; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Laskowski J; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Li HY; Department of Medicine, University of Colorado Denver, Aurora, Colorado.; Veterans Affairs Medical Center, Denver, Colorado., McSharry MV; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Sippel TR; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Bullock BL; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Johnson AM; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Poczobutt JM; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Neuwelt AJ; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Malkoski SP; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Weiser-Evans MC; Department of Medicine, University of Colorado Denver, Aurora, Colorado.; Department of Pharmacology, University of Colorado Denver, Aurora, Colorado., Lambris JD; Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado., Clambey ET; Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado., Thurman JM; Department of Medicine, University of Colorado Denver, Aurora, Colorado., Nemenoff RA; Department of Medicine, University of Colorado Denver, Aurora, Colorado. Raphael.Nemenoff@ucdenver.edu.; Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Jan 01; Vol. 78 (1), pp. 143-156. Date of Electronic Publication: 2017 Nov 08.
DOI:	10.1158/0008-5472.CAN-17-0240
Abstrakt:	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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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