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Cancer Cell. 2018 Oct 8;34(4):561-578.e6. doi: 10.1016/j.ccell.2018.09.003.

Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy.

Author information

1
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Knight Cancer Research Building Room 3030, 2720 SW Moody Avenue, #KC-CDCB, Portland, OR 97201-5042, USA.
2
Department of Biomedical Engineering, Program in Computational Biology, Oregon Health & Science University, Portland, OR 97239, USA.
3
Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA.
4
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Knight Cancer Research Building Room 3030, 2720 SW Moody Avenue, #KC-CDCB, Portland, OR 97201-5042, USA; Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
5
Department of Biomedical Engineering, Program in Computational Biology, Oregon Health & Science University, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
6
Department of Anatomy, Helen Diller Family Comprehensive Cancer Center, Parker Immunotherapy Cancer Institute, University of California, San Francisco, CA 94143, USA.
7
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Knight Cancer Research Building Room 3030, 2720 SW Moody Avenue, #KC-CDCB, Portland, OR 97201-5042, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: coussenl@ohsu.edu.

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.

KEYWORDS:

CD8(+) T cell; complement C5a; immunotherapy; inflammation; macrophage; squamous cell carcinoma; urokinase

PMID:
30300579
PMCID:
PMC6246036
[Available on 2019-10-08]
DOI:
10.1016/j.ccell.2018.09.003

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