Ovarian cancer-associated ascites demonstrates altered immune environment: implications for antitumor immunity.
BACKGROUND
To identify immunosuppressive elements present in ovarian cancer associated ascites.


METHODS
Ascites and plasma were obtained from ovarian, primary peritoneal or fallopian tube cancer patients. Surface markers were identified by fluorescence-activated cell sorting (FACS). Cytokine and chemokine concentrations were measured with LINCOplex microarrays. Antigen-specific T-lymphocytes from ascites and plasma were expanded with artificial antigen-presenting cells (aAPC). Cell-mediated immune response was assessed with chromium release assays.


RESULTS
Samples were collected from 37 patients with advanced ovarian cancer. FACS was performed on 27 ascites specimens. A low CD4/CD8 ratio (<1.6) was seen in 13 patient samples and associated with significantly improved overall survival (p=0.040). LINCOplex evaluation of 22 paired ascites and plasma samples demonstrated significantly elevated levels of IL-6, IL-8, IL-10, IL-15, IP-10, MCP-1, MIP-1beta and VEGF and significantly reduced levels of IL-2, IL-5, IL-7, IL-17, PDGF-BB, and RANTES in ascites compared to plasma (p<0.05). Autologous ovarian cancer cell lysis with T-lymphocytes from ascites was limited. Although aAPC stimulation resulted in effective expansion of antigen specific T-cells from peripheral lymphocytes (35-fold), only limited expansion was noted from ascites-derived lymphocytes (10-fold).


CONCLUSIONS
Ovarian cancer-associated ascites may provide an immunosuppressive environment. A high CD4/CD8 ratio, which may indicate the presence of regulatory T-cells, is associated with poor outcome. Reduced IL-2 and elevated IL-6 and IL-10 levels favor a Th2 inhibitory immune response. This immunosuppressive climate may explain our observation of non responsiveness in ascites derived T-cells.
Giuntoli
Robert L
RL
The Kelly Gynecologic Oncology Service, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Phipps #281, Baltimore, Maryland 21287, USA. rgiunto1@jhmi.edu
Webb
Tonya J
TJ
Zoso
Alessia
A
Rogers
Ophelia
O
Diaz-Montes
Teresa P
TP
Bristow
Robert E
RE
Oelke
Mathias
M
D018262:Adenocarcinoma, Clear Cell / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001201:Ascites / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002857:Chromium / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D016207:Cytokines / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D005185:Fallopian Tube Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; D002857:Chromium