Complement Activation via a C3a Receptor Pathway Alters CD4 + T Lymphocytes and Mediates Lung Cancer Progression

Cancer Res. 2018 Jan 1;78(1):143-156. doi: 10.1158/0008-5472.CAN-17-0240. Epub 2017 Nov 8.

Abstract

The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ+/TNFα+/IL10+ CD4+ and CD8+ T cells. Immunodepletion of CD4+ but not CD8+ T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway.Significance: This provocative study suggests that inhibiting complement activation may heighten immunotherapeutic responses in lung cancer, offering findings with immediate implications, given the existing clinical availability of complement antagonists. Cancer Res; 78(1); 143-56. ©2017 AACR.

Publication types

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

MeSH terms

  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Complement Activation*
  • Complement C3 / genetics
  • Complement C3d / metabolism
  • Female
  • Humans
  • Immunoglobulin M / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oncogene Proteins, Fusion / genetics
  • Receptors, Complement / immunology*
  • Receptors, Complement / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Complement C3
  • EML4-ALK fusion protein, human
  • Immunoglobulin M
  • Oncogene Proteins, Fusion
  • Receptors, Complement
  • complement C3a receptor
  • Complement C3d