title: T helper responses are maintained by basal-like breast cancer cells and confer to immune modulation via upregulation of PD-1 ligands.
abstract: A conspicuous T cell infiltration is frequently observed in triple-negative and/or basal-like breast cancers. Since the immunological course of breast cancer is explicitly directed by helper T cells, this study aims to determine the influence of basal-like breast cancer (BLBC) cells on CD4(+) T cell responses. Co-cultures were established with breast cancer cell lines and CD4(+) T cells under stimulatory conditions. Helper T cell activation, proliferation, cytokine secretion, and differentiation were assessed. Protein and mRNA expression of PD-1 ligands were determined on breast cancer cell lines. Blockade assays were performed in order to determine the functional assets of PD-1 ligation. In contrast to luminal breast cancer cells, BLBC cells allowed CD4(+) T cell activation, proliferation, and IFN-γ secretion, but only to a certain extent. A substantial population of CD25(+)CD127(low/-) regulatory T (Treg) cells was also induced in BLBC co-cultures. In return, IFN-γ stimulated the upregulation of PD-L1 (B7-H1) and/or PD-L2 (B7-DC) inhibitory molecules on the basal-like cells. In prolonged periods of co-culturing, blockade of PD-1 ligands on BLBC cell lines impaired Treg differentiation, restored IL-2 secretion, and increased CD8(+) T cell activation. In conclusion, T helper responses were maintained by BLBC cells. On the other hand, IFN-γ secreted from Th1 and other immune cells upregulated the expression of PD-1 ligands on BLBC cells and modulated the immune reactions. Our results indicate the capacity of BLBCs to adapt to IFN-γ-mediated anti-tumor immune responses and to evade immunity via upregulation of PD-1 ligands.
authors.affiliation: Department of Basic Oncology, Hacettepe University Cancer Institute, 06100, Sihhiye, Ankara, Turkey.
authors.forename: Pinar
authors.initials: P
authors.lastname: Karasar
authors.forename: Gunes
authors.initials: G
authors.lastname: Esendagli
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D061986:MCF-7 Cells; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000096:biosynthesis*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma