title: Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells.
abstract: Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.
authors.affiliation: Department of Microbiology and Immunology, VCU School of Medicine, Massey Cancer Center, Richmond, VA 23298, USA.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Morales
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.forename: Laura
authors.initials: L
authors.lastname: Graham
authors.forename: Marta
authors.initials: M
authors.lastname: Feldmesser
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001973:Bromodeoxyuridine; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D018719:Erb-b2 Receptor Tyrosine Kinases