Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth

PLoS One. 2009 Sep 10;4(9):e6982. doi: 10.1371/journal.pone.0006982.


Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.

Methods and findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies.

Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cyclophosphamide / pharmacology*
  • Female
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / cytology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*


  • Antineoplastic Agents
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Interferon-gamma
  • Cyclophosphamide