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


RESULTS
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
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.


BACKGROUND
clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887.
Comin-Anduix
Begoña
B
Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America. bcomin@mednet.ucla.edu
Sazegar
Hooman
H
Chodon
Thinle
T
Matsunaga
Douglas
D
Jalil
Jason
J
von Euw
Erika
E
Escuin-Ordinas
Helena
H
Balderas
Robert
R
Chmielowski
Bartosz
B
Gomez-Navarro
Jesus
J
Koya
Richard C
RC
Ribas
Antoni
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000187:drug effects*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab