In vivo administration of artificial antigen-presenting cells activates low-avidity T cells for treatment of cancer.
The development of effective antitumor immune responses is normally constrained by low-avidity, tumor-specific CTLs that are unable to eradicate the tumor. Strategies to rescue antitumor activity of low-avidity melanoma-specific CTLs in vivo may improve immunotherapy efficacy. To boost the in vivo effectiveness of low-avidity CTLs, we immunized mice bearing lung melanoma metastases with artificial antigen-presenting cells (aAPC), made by covalently coupling (pep)MHC-Ig dimers and B7.1-Ig molecules to magnetic beads. aAPC treatment induced significant tumor reduction in a mouse telomerase antigen system, and complete tumor eradication in a mouse TRP-2 antigen system, when low-avidity CTLs specific for these antigens were adoptively transferred. In addition, in an in vivo treatment model of subcutaneous melanoma, aAPC injection also augmented the activity of adoptively transferred CTLs and significantly delayed tumor growth. In vivo tumor clearance due to aAPC administration correlated with in situ proliferation of the transferred CTL. In vitro studies showed that aAPC effectively stimulated cytokine release, enhanced CTL-mediated lysis, and TCR downregulation in low-avidity CTLs. Therefore, in vivo aAPC administration represents a potentially novel approach to improve cancer immunotherapy.
Ugel
Stefano
S
Department of Oncology, Oncology Section, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy.
Zoso
Alessia
A
De Santo
Carmela
C
Li
Yu
Y
Marigo
Ilaria
I
Zanovello
Paola
P
Scarselli
Elisa
E
Cipriani
Barbara
B
Oelke
Mathias
M
Schneck
Jonathan P
JP
Bronte
Vincenzo
V
D000818:Animals; D000915:Antibody Affinity; D000938:Antigen-Presenting Cells / Q000276:immunology*; D048708:Cell Growth Processes / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology