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Immunology |
1 The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea; 2 Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri; 3 LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and 4 National Cancer Center, Goyang-Si, Gyeonggi-do, Korea
Requests for reprints: Byoung S. Kwon, The Immunomodulation Research Center, University of Ulsan, Ulsan 680-749, Korea. Phone: 82-52-259-2874; Fax: 82-52-259-2740; E-mail: bskwon{at}mail.ulsan.ac.kr.
Anti-4-1BB–mediated anticancer effects were potentiated by depletion of CD4+ cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8+ T cells into IFN-
–producing CD11c+CD8+ T cells. The CD4+ cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO)+ dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D+KLRG1+CD11c+CD8+ T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8+ T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment. [Cancer Res 2007;67(18):8891–9]
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