IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

Cell Death Differ. 2009 May;16(5):708-18. doi: 10.1038/cdd.2008.197. Epub 2009 Jan 30.


IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8(+) T cells. MV induced significant CD8(+) T-cell apoptosis, as evidenced by Annexin binding (64.4+/-6.4%), caspase activation (58.1+/-7.6%), a loss of mitochondrial membrane potential (82.9+/-3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRzeta chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P<0.005-0.05), prevented cytochrome c release and Bid cleavage, and concurrently restored the expression of Bcl-2, Bcl-xL, FLIP and Mcl-1 (P<0.005-0.01) in T cells. In addition, IRX-2 reversed MV-induced inhibition of the PI3K/Akt pathway. An Akt inhibitor (Akti-1/2) abrogated protective effects of IRX-2, suggesting that Akt is a downstream target of IRX-2 signaling. Thus, ex vivo pretreatment of CD8(+) T cells with IRX-2 provided potent protection from tumor-induced apoptosis. IRX-2 application to future cancer biotherapies could improve their effectiveness by bolstering T-cell resistance to tumor-induced immunosuppression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Bcl-2-Like Protein 11
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Janus Kinase 3 / metabolism
  • Jurkat Cells
  • Membrane Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT5 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • Time Factors
  • bcl-2-Associated X Protein / metabolism


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Cytokines
  • IRX 2
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • STAT5 Transcription Factor
  • bcl-2-Associated X Protein
  • Phosphatidylinositol 3-Kinases
  • JAK3 protein, human
  • Janus Kinase 3
  • Proto-Oncogene Proteins c-akt