title: Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells.
abstract: Two major barriers in the immunotherapy of breast cancer include tumor-induced immune suppression and the establishment of long-lasting immune responses against the tumor. Recently, we demonstrated in an animal model of breast carcinoma that expanding and reprogramming tumor-sensitized lymphocytes, ex vivo, yielded T memory (Tm) cells as well as activated CD25+ NKT cells and NK cells. The presence of activated CD25+ NKT and NK cells rendered reprogrammed T cells resistant to MDSC-mediated suppression, and adoptive cellular therapy (ACT) of reprogrammed lymphocytes protected the host from tumor development and relapse. Here, we performed a pilot study to determine the clinical applicability of our protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients, ex vivo. We show that bryostatin 1 and ionomycin combined with IL-2, IL-7, and IL-15 can expand and reprogram tumor-sensitized PBMCs. Reprogrammed lymphocytes contained activated CD25+ NKT and NK cells as well as Tm cells and displayed enhanced reactivity against HER-2/neu in the presence of MDSCs. The presence of activated NKT cells was highly correlated with the rescue of anti-HER-2/neu immune responses from MDSC suppression. Ex vivo blockade experiments suggest that the NKG2D pathway may play an important role in overcoming MDSC suppression. Our results show the feasibility of reprogramming tumor-sensitized immune cells, ex vivo, and provide rationale for ACT of breast cancer patients.
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Box 980035, 401 College Street, Richmond, VA, 23298, USA.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.forename: Christine K
authors.initials: CK
authors.lastname: Zoon
authors.forename: Wen
authors.initials: W
authors.lastname: Wan
authors.forename: Khin
authors.initials: K
authors.lastname: Marlar
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Keim
authors.forename: Mehrab Nasiri
authors.initials: MN
authors.lastname: Kenari
authors.forename: A Latif
authors.initials: AL
authors.lastname: Kazim
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
mesh_terms: D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D054713:Bryostatins / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D054713:Bryostatins; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D015759:Ionomycin; D018719:Erb-b2 Receptor Tyrosine Kinases; C046785:bryostatin 1