Abstract
Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA)+ macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1+ mast cells and macrophages, including suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3+ effector memory CD8+ T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy. Medler et al. find that C3-independent C5a release mediated by uPA+ macrophages fosters an immunosuppressive microenvironment during squamous carcinogenesis by activating C5aR1+ mast cells and macrophages. C5aR1 inhibition improves paclitaxel efficacy by reprogramming macrophages to recruit cytotoxic CD8+ T cells.
Original language | English (US) |
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Pages (from-to) | 561-578.e6 |
Journal | Cancer Cell |
Volume | 34 |
Issue number | 4 |
DOIs | |
State | Published - Oct 8 2018 |
Keywords
- CD8 T cell
- complement C5a
- immunotherapy
- inflammation
- macrophage
- squamous cell carcinoma
- urokinase
ASJC Scopus subject areas
- Oncology
- Cancer Research