Arming tumor-reactive T cells with costimulator B7-1 enhances therapeutic efficacy of the T cells.
T cells ectopically expressing costimulators are pathogenic and contribute to autoimmunity against self-antigens. Given that tumor antigens are often self-antigen or mutated self-antigens, we hypothesize that neoexpressing a costimulator on tumor-reactive T cells may likewise enhance their reactivity to tumor. To test this hypothesis, we have expressed B7-1 on OT-1 CD8+ T-cell receptor transgenic T cells via protein transfer (or protein "painting"). Naïve OT-1 T cells, after being painted with B7-1, can self-costimulate themselves, elicit enhanced proliferative and CTL responses to E.G7-ovalbumin tumor cells (expressing a cognate antigen), and become resistant to CD4+CD25+ regulatory T-cell-mediated suppression. Importantly, these T cells, when coimplanted with E.G7-ovalbumin tumor cells into a syngeneic host, are three to nine times more potent than are control T cells (mock painted with human IgG) in inhibiting tumor growth. Further, on transfer into mice bearing established E.G7-ovalbumin tumors, B7-1-painted ex vivo-amplified OT-1 T cells induced complete tumor regression in 65% of treated mice, whereas the control T cells did so in only 28% of treated mice. Finally, on transfer into mice bearing less immunogenic 4T1 breast tumors, B7-1-painted tumor-reactive CD8+ T cells improved the survival of treated mice to a greater extent than did the control T cells. Hence, this study establishes that arming tumor-reactive T cells with a costimulator can enhance their antitumor efficacy.
Zheng
Guoxing
G
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL 61107, USA. guoxingz@uic.edu
Liu
Shanrong
S
Wang
Peijie
P
Xu
Ying
Y
Chen
Aoshuang
A
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D015202:Protein Engineering / Q000379:methods
D018122:B7-1 Antigen