title: Three-dimensional scaffolds to evaluate tumor associated fibroblast-mediated suppression of breast tumor specific T cells.
abstract: In the tumor microenvironment, the signals from tumor-associated fibroblasts (TAF) that suppress antitumor immunity remain unclear. Here, we develop and investigate an in vitro three-dimensional (3D) scaffold model for the novel evaluation of TAF interaction with breast tumor cells and breast specific, neu antigen (p98) reactive T cells. Breast cancer cells seeded on 3D chitosan-alginate (CA) scaffolds showed productive growth and formed distinct tumor spheroids. Antigen specific p98 T cells, but not naïve T cells, bound significantly better to tumor cells on scaffolds. The p98 T cells induced potent tumor cell killing but T helper cell cytokine function was impaired in the presence of TAF coseeding on scaffolds. We found that the immunosuppression was mediated, in part, by transforming growth factor beta (TGF-b) and interleukin-10 (IL-10). Therefore, TAF appear capable of inducing potent T cell suppression. CA scaffolds can provide clinically relevant findings prior to preclinical testing of novel immunotherapies.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98109, United States.
authors.forename: Vy
authors.initials: V
authors.lastname: Phan-Lai
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Florczyk
authors.forename: Forrest M
authors.initials: FM
authors.lastname: Kievit
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.forename: Ekram
authors.initials: E
authors.lastname: Gad
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Miqin
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000464:Alginates / Q000737:chemistry; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048271:Chitosan / Q000737:chemistry; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D056747:Immunomodulation; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D054457:Tissue Scaffolds; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000464:Alginates; D000951:Antigens, Neoplasm; C508609:IL10 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D048271:Chitosan