Increased pressure stimulates aberrant dendritic cell maturation.
Patients with malignancy typically exhibit abnormal dendritic cell profiles. Interstitial tumor pressure is increased 20-50 mmHg over that in normal tissue. We hypothesized that elevated pressure in the tumor microenvironment may influence dendritic cell (DC) phenotype and function. Monocyte-derived immature and mature DC isolated from healthy human donors were exposed to either ambient or 40 mmHg increased pressure at 37 degrees C for 12 hours, then assessed for expression of CD80, CD86, CD83, CD40, MHC-I and MHC-II. IL-12 production and phagocytosis of CFSE-labeled tumor lysate were assessed in parallel. Elevated pressure significantly increased expression of all co-stimulatory and MHC molecules on mature DC. Immature DC significantly increased expression of CD80, CD86, CD83 and MHC-II, but not MHC-I and CD40, versus ambient pressure controls. Pressure-treated immature DC phenotypically resembled mature DC controls, but produced low IL-12. Phenotypic maturation correlated with decreased phagocytic capacity. These results suggest increased extracellular pressure may cause aberrant DC maturation and impair tumor immunosurveillance.
Craig
David H
DH
Department of Surgery, John D. Dingell VA Medical Center and Wayne State University, 4646 John R. Street, Detroit, MI 48201, USA.
Schaubert
Keri L
KL
Shiratsuchi
Hiroe
H
Kan-Mitchell
June
J
Basson
Marc D
MD
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology*; D005110:Extracellular Space / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D010587:Phagocytosis; D010641:Phenotype; D011312:Pressure
D006649:Histocompatibility Antigens; D018664:Interleukin-12