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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • Carcinogenesis / drug effects*
  • Carcinoma, Squamous Cell / drug therapy
  • Complement C5a / drug effects*
  • Disease Models, Animal
  • Drug Therapy* / methods
  • Humans
  • Macrophages / drug effects
  • Macrophages / physiology
  • Mice
  • Receptor, Anaphylatoxin C5a / drug effects*
  • Signal Transduction / drug effects


  • C5ar1 protein, mouse
  • Receptor, Anaphylatoxin C5a
  • Complement C5a