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D. Ajona
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-007 - Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis (ID 8958)
09:30 - 09:30 | Author(s): D. Ajona
- Abstract
Background:
The complement system, a central part of innate immunity, is implicated in the maintenance of a favorable microenvironment for lung cancer progression. In particular, several studies have demonstrated a tumor-promoting role for the immune regulator C5a, but its direct impact on growth and dissemination of lung cancer cells is poorly understood. In this study we aimed to investigate the contribution of the C5a/C5aR1(CD88) axis to the malignant phenotype of NSCLC cells, particularly to skeletal colonization, a preferential lung metastasis site.
Method:
The association between C5aR1 expression and clinical outcome was assessed at both the mRNA and protein levels by in silico and immunohistochemistry analyses, respectively. The mRNA levels of C5aR1 were also determined in a panel of 45 cell lines representing the main lung cancer subtypes. The expression of the receptor was validated by flow cytometry. The functional significance of C5aR1 expression in NSCLC cells was evaluated using lentiviral gene silencing and drug inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity and osteoclastogenesis were also performed.
Result:
High levels of C5aR1 in primary human NSCLC tumors were significantly associated with shorter recurrence-free survival and overall survival both at the mRNA and protein levels. Many lung cancer cell lines expressed C5aR1 mRNA. C5aR1 was also detected by flow cytometry on the cell surface of representative lung cancer cell lines. Moreover, addition of C5a to cultured cells led to phosphorylation of p42/44 MAPK and translocation of NF-kB to the nucleus, demonstrating the functionality of the receptor. Silencing of C5aR1 in A549 and H460 lung cancer cells did not affect proliferation, but led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. C5aR1 pharmacological blockade also reduced the osseous metastatic activity of lung cancer cells in vivo. Moreover, metalloproteolytic, migratory and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. This effect was associated with decreased osteoclastogenic activity in vitro, which was rescued by exogenous addition of the chemokine CXCL16.
Conclusion:
Disruption of C5aR1 signaling in lung cancer cells abrogates osseous colonization through a CXCL16-mediated mechanism. This study reinforces the role played by the C5a/C5aR1 axis in lung cancer progression, and supports its potential use as a novel therapeutic target.
