| Literature DB >> 30300579 |
Terry R Medler1, Dhaarini Murugan1, Wesley Horton2, Sushil Kumar1, Tiziana Cotechini1, Alexandra M Forsyth1, Patrick Leyshock2, Justin J Leitenberger3, Molly Kulesz-Martin4, Adam A Margolin5, Zena Werb6, Lisa M Coussens7.
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.Entities:
Keywords: CD8(+) T cell; complement C5a; immunotherapy; inflammation; macrophage; squamous cell carcinoma; urokinase
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Year: 2018 PMID： 30300579 PMCID： PMC6246036 DOI： 10.1016/j.ccell.2018.09.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743