Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma.
OBJECTIVE
Immunotherapeutic modalities are commonly used for treatment of patients with melanoma. The therapeutic success in preclinical models has not yielded the expected clinical results. To understand this discrepancy, we attempted to define immune homeostasis of 209 patients with melanoma across stages of disease relative to normal controls.


METHODS
Peripheral blood mononuclear cells (PBMC) and plasma were collected from patients and healthy donors. PBMC were analyzed for frequencies of natural killer, dendritic, and T cells and their functional status. Matched plasma samples were analyzed for the concentrations of 27 cytokines, chemokines, and growth factors. RNA was isolated from 24 metastatic melanoma tumor biopsies and profiled by microarray analysis.


RESULTS
The frequency of natural killer, T, and dendritic cells in patients does not significantly change across stages of melanoma. However, plasma concentrations of Th2 cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] in tumor-bearing patients were significantly higher than those with resected melanoma. Expression array analysis of metastatic melanoma revealed that the malignant melanocytes were not the source of the Th2 cytokines but did highly up-regulate vascular endothelial growth factor (VEGF) transcripts, consistent with plasma VEGF concentrations. In vitro VEGF exposure of normal PBMC lead to repolarization from Th1 to Th2 emulating the state of metastatic melanoma.


CONCLUSIONS
Patients with metastatic melanoma exist in a state of Th2-mediated "chronic inflammation" as a result of at least VEGF overproduction by malignant tumors. These data support prior observations regarding the effect of VEGF on immune cell function and suggests consideration of VEGF inhibitors in future cancer immunotherapy clinical studies in metastatic melanoma.
Nevala
Wendy K
WK
Division of Hematology, Department of Internal Medicine, Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Vachon
Celine M
CM
Leontovich
Alexey A
AA
Scott
Christopher G
CG
Thompson
Michael A
MA
Markovic
Svetomir N
SN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D018418:Th2 Cells / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A