Tumor cyclooxygenase 2-dependent suppression of dendritic cell function.
Dendritic cells (DCs) serve as professional antigen-presenting cells and are pivotal in the host immune response to tumor antigens. To define the pathways limiting DC function in the tumor microenvironment, we assessed the impact of tumor cyclooxygenase (COX)-2 expression on DC activities. Bone marrow-derived DCs were cultured in either tumor supernatant (TSN) or TSN from COX-2-inhibited tumors. After culture, DCs were pulsed with tumor-specific peptides, and their ability to generate antitumor immune responses was assessed following injection into established murine lung cancer. In vitro, DC phenotype, alloreactivity, antigen processing and presentation, and interleukin (IL)-10 and IL-12 secretion were evaluated. DCs cultured in TSN failed to generate antitumor immune responses and caused immunosuppressive effects that correlated with enhanced tumor growth. However, genetic or pharmacological inhibition of tumor COX-2 expression restored DC function and effective antitumor immune responses. Functional analyses indicated that TSN causes a decrement in DC capacity to (a) process and present antigens, (b) induce alloreactivity, and (c) secrete IL-12. Whereas TSN DCs showed a significant reduction in cell surface expression of CD11c, DEC-205, MHC class I antigen, MHC class II antigen, CD80, and CD86 as well as a reduction in the transporter-associated proteins, transporter associated with antigen processing 1 and 2, the changes in phenotype and function were not evident when DCs were cultured in supernatant from COX-2-inhibited tumors. We conclude that inhibition of tumor COX-2 expression or activity can prevent tumor-induced suppression of DC activities.
Sharma
Sherven
S
University of California Los Angeles School of Medicine-Wadsworth Pulmonary Immunology Laboratory, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Stolina
Marina
M
Yang
Seok-Chul
SC
Baratelli
Felicita
F
Lin
Jeff F
JF
Atianzar
Kimberly
K
Luo
Jie
J
Zhu
Li
L
Lin
Ying
Y
Huang
Min
M
Dohadwala
Mariam
M
Batra
Raj K
RK
Dubinett
Steven M
SM
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology; D008214:Lymphocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D010455:Peptides; D016753:Interleukin-10; D018664:Interleukin-12; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases