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 Margolin, Zena Werb, Lisa Coussens

Research output: Contribution to journalArticle

10 Citations (Scopus)

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

Fingerprint

Complement C5a
Carcinogenesis
Macrophages
T-Lymphocytes
Drug Therapy
Paclitaxel
Mast Cells
Urokinase-Type Plasminogen Activator
Immunosuppressive Agents
Humoral Immunity
Immunotherapy
Transgenic Mice
Neoplasms
Carcinoma
Peptides

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy. / Medler, Terry R.; Murugan, Dhaarini; Horton, Wesley; Kumar, Sushil; Cotechini, Tiziana; Forsyth, Alexandra M.; Leyshock, Patrick; Leitenberger, Justin J.; Kulesz-Martin, Molly; Margolin, Adam; Werb, Zena; Coussens, Lisa.

In: Cancer Cell, Vol. 34, No. 4, 08.10.2018, p. 561-578.e6.

Research output: Contribution to journalArticle

Medler, TR, Murugan, D, Horton, W, Kumar, S, Cotechini, T, Forsyth, AM, Leyshock, P, Leitenberger, JJ, Kulesz-Martin, M, Margolin, A, Werb, Z & Coussens, L 2018, 'Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy', Cancer Cell, vol. 34, no. 4, pp. 561-578.e6. https://doi.org/10.1016/j.ccell.2018.09.003
Medler, Terry R. ; Murugan, Dhaarini ; Horton, Wesley ; Kumar, Sushil ; Cotechini, Tiziana ; Forsyth, Alexandra M. ; Leyshock, Patrick ; Leitenberger, Justin J. ; Kulesz-Martin, Molly ; Margolin, Adam ; Werb, Zena ; Coussens, Lisa. / Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy. In: Cancer Cell. 2018 ; Vol. 34, No. 4. pp. 561-578.e6.
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