CD277 is a negative co-stimulatory molecule universally expressed by ovarian cancer microenvironmental cells.
CD277, a member of the butyrophilin subfamily 3 (BTN3), shares significant sequence similarities and predicted common structural features with inhibitory B7-H4 and other members of the B7 superfamily. Here we report that CD277 is consistently expressed in stromal, as well as tumor cells in the microenvironment of human advanced ovarian carcinoma specimens, both of primary and metastatic origin. MHC-II+ myeloid antigenpresenting leukocytes (dendritic cells and macrophages) express significantly higher levels of surface CD277, compared to other tumor-infiltrating leukocyte subsets, and this expression is significantly up-regulated by multiple common tumor microenvironmental signals, including VEGF and CCL3. Most importantly, engagement of CD277 on the surface of TCR-stimulated T cells inhibits their otherwise robust expansion and production of Th1 cytokines by preventing the up-regulation of cFLIP. Our results point to a role for CD277 up-regulated by microenvironmental signals in the acquisition of a regulatory phenotype by tumor-associated myeloid cells. Consequently, CD277, and likely other butyrophilins and butyrophilin-like molecules, emerge as regular players in the orchestration of immunosuppressive networks in ovarian cancer, and therefore new targets for interventions to overcome immune evasion and boost anti-tumor immunity in cancer patients.
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Juan R
JR
Cubillos-Ruiz
Diana
D
Martinez
Uciane K
UK
Scarlett
Melanie R
MR
Rutkowski
Yolanda C
YC
Nesbeth
Ana L
AL
Camposeco-Jacobs
Jose R
JR
Conejo-Garcia
D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071797:Butyrophilins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020014:K562 Cells; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D011487:Protein Conformation; D017154:Stromal Cells / Q000276:immunology* / Q000473:pathology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D059016:Tumor Microenvironment
D015703:Antigens, CD; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016207:Cytokines; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins