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PLoS One. 2010 Sep 15;5(9):e12711. doi: 10.1371/journal.pone.0012711.

Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma.

Author information

1
Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America. bcomin@mednet.ucla.edu

Abstract

BACKGROUND:

The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma.

METHODOLOGY/PRINCIPAL:

Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response.

CONCLUSIONS/SIGNIFICANCE:

The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade.

CLINICAL TRIAL REGISTRATION:

clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.

PMID:
20856802
PMCID:
PMC2939876
DOI:
10.1371/journal.pone.0012711
[Indexed for MEDLINE]
Free PMC Article

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