title: Tumor cyclooxygenase 2-dependent suppression of dendritic cell function.
abstract: 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.
authors.affiliation: University of California Los Angeles School of Medicine-Wadsworth Pulmonary Immunology Laboratory, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Seok-Chul
authors.initials: SC
authors.lastname: Yang
authors.forename: Felicita
authors.initials: F
authors.lastname: Baratelli
authors.forename: Jeff F
authors.initials: JF
authors.lastname: Lin
authors.forename: Kimberly
authors.initials: K
authors.lastname: Atianzar
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Mariam
authors.initials: M
authors.lastname: Dohadwala
authors.forename: Raj K
authors.initials: RK
authors.lastname: Batra
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: 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
chemical_list: 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