Related Experiment Video
Updated: Jun 8, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma
Begoña Comin-Anduix1, Hooman Sazegar, Thinle Chodon
1Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America. bcomin@mednet.ucla.edu
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.
Insights
Tremelimumab, a CTLA4-blocking antibody, alters cell signaling in patients with metastatic melanoma. Monocyte signaling changes suggest their role in treatment response.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Investigated the impact of CTLA4 blockade with tremelimumab on cell signaling networks.
- Utilized peripheral blood mononuclear cell (PBMC) samples from metastatic melanoma patients.
Purpose of the Study:
- To understand the effects on cell signaling pathways after CTLA4 blockade.
- To explore the role of specific cell subsets in response to tremelimumab treatment.
Main Methods:
- Employed intracellular flow cytometry to detect phosphorylated signaling molecules.
- Analyzed signaling downstream of the T cell receptor (TCR) and cytokine receptors.
Main Results:
- Observed increased pp38, pSTAT1, and pSTAT3, with decreased pLck, pERK1/2, and pSTAT5 in PBMCs.
- Detected these signaling changes in CD4, CD8 T lymphocytes, and CD14 monocytes.
- Noted divergent phosphorylation patterns in Zap70, LAT, Akt, and STAT6 based on tumor response.
Conclusions:
- Tremelimumab administration modulates TCR and cytokine receptor signaling in T cells and monocytes.
- Significant signaling modulation in monocytes indicates their potential involvement in clinical responses to CTLA4 blockade.
