Choi Beom K, Kim Young H, Kang Woo J, Lee Sun K, Kim Kwang H, Shin Su M, Yokoyama Wayne M, Kim Tae Y, Kwon Byoung S
The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea.
Cancer Res. 2007 Sep 15;67(18):8891-9. doi: 10.1158/0008-5472.CAN-07-1056.
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-gamma-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.
在携带B16F10黑色素瘤的C57BL/6小鼠中，CD4+细胞的耗竭增强了抗4-1BB介导的抗癌作用。抗4-1BB诱导多克隆肿瘤特异性CD8+ T细胞扩增并分化为产生IFN-γ的CD11c+CD8+ T细胞。CD4+细胞耗竭有助于免疫细胞浸润肿瘤组织，并消除一些调节性障碍，如调节性T细胞和吲哚胺-2,3-双加氧酶（IDO）+树突状细胞。两种单克隆抗体（mAb）均有助于在体内有效诱导肿瘤细胞上的MHC I类分子。介导抗4-1BB效应的效应细胞是优先在肿瘤组织中积累的NKG2D+KLRG1+CD11c+CD8+ T细胞。阻断NKG2D可使治疗效果降低20%至26%，这可能表明NKG2D部分有助于分化的CD8+ T细胞杀伤肿瘤。我们的结果表明，激动性抗4-1BB和耗竭性抗CD4这两种mAb联合使用，可增强高效肿瘤杀伤性CTL的产生，促进其浸润，并产生易感的肿瘤微环境。
