title: A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells.
abstract: In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine-enriched (IL-2 and IFN-γ) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+ /CD11b+ /CD14- /HLA-DR- MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P < 0.001), IFN-γ production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and T(reg) differentiation, and presence of Th() cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, 723 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI 48201, USA. thakur@karmanos.org
authors.forename: Archana
authors.initials: A
authors.lastname: Thakur
authors.forename: Dana
authors.initials: D
authors.lastname: Schalk
authors.forename: Sanila H
authors.initials: SH
authors.lastname: Sarkar
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Khadimi
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Lum
mesh_terms: D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D022423:Myeloid Cells / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058408:Th1-Th2 Balance / Q000187:drug effects; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D007376:Interleukin-2; D007371:Interferon-gamma