期刊
CANCER CELL
卷 34, 期 4, 页码 561-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.09.003
关键词
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资金
- American Cancer Society - Friends of Robert Kinas Postdoctoral Fellowship [PF-14-221-01-MPC]
- NIH/NCI Postdoctoral Training Grant [CA106195]
- Cathy and Jim Rudd Career Development Award for Cancer Research
- Medical Research Foundation
- NIH/NCI [CA192405, CA057621, CA130980, CA155331, CA163123]
- DOD BCRP Era of Hope Scholar Expansion Award [W81XWH-08-PRMRP-IIRA]
- Susan G. Komen Foundation [KG110560]
- Breast Cancer Research Foundation
- Brenden-Colson Center for Pancreatic Health
- Stand Up To Cancer - Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant [SU2C-AACR-DT14-14]
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 IFN gamma. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.
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