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

Terry R. Medler, Dhaarini Murugan, Wesley Horton, Sushil Kumar, Tiziana Cotechini, Alexandra M. Forsyth, Patrick Leyshock, Justin J. Leitenberger, Molly Kulesz-Martin, Adam A. Margolin, Zena Werb, Lisa M. Coussens

Research output: Contribution to journalArticle

33 Scopus citations

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. Medler et al. find that C3-independent C5a release mediated by uPA+ macrophages fosters an immunosuppressive microenvironment during squamous carcinogenesis by activating C5aR1+ mast cells and macrophages. C5aR1 inhibition improves paclitaxel efficacy by reprogramming macrophages to recruit cytotoxic CD8+ T cells.

Original languageEnglish (US)
Pages (from-to)561-578.e6
JournalCancer Cell
Volume34
Issue number4
DOIs
StatePublished - Oct 8 2018

Keywords

  • CD8 T cell
  • complement C5a
  • immunotherapy
  • inflammation
  • macrophage
  • squamous cell carcinoma
  • urokinase

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Medler, T. R., Murugan, D., Horton, W., Kumar, S., Cotechini, T., Forsyth, A. M., Leyshock, P., Leitenberger, J. J., Kulesz-Martin, M., Margolin, A. A., Werb, Z., & Coussens, L. M. (2018). Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy. Cancer Cell, 34(4), 561-578.e6. https://doi.org/10.1016/j.ccell.2018.09.003