Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy.
Cancer Cell
; 34(4): 561-578.e6, 2018 10 08.
Article
em En
| MEDLINE
| ID: mdl-30300579
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.
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MEDLINE
Assunto principal:
Complemento C5a
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Receptor da Anafilatoxina C5a
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Tratamento Farmacológico
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Carcinogênese
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article