CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell-and IL-2-dependent mechanism

A tumor-specific CD8(+) T cell response was studied using adoptive transfer of OT-I TCR transgenic cells. Upon i.p. challenge with E.G7 tumor, OT-1 cells undergo CD4(+) T cell-independent expansion at the tumor site and develop lytic function. Before tumor elimination, however, they leave the peritoneal cavity (PC) and appear in the LN and spleen where they exhibit "split anergy" and cannot further proliferate to antigen. Administering anti-CTLA-4 mAb early caused sustained OT-1 expansion in the PC, and late administration caused the OT-1 cells to return to the PC and further expand; in both cases, tumor was controlled. These effects required CD4(+) T cells and IL-2 and appear to result from reversal of the nonresponsive state of the CD8(+) T cells.

利用过继转移OT - I TCR转基因细胞研究了肿瘤特异性CD8(+) T细胞应答。在腹腔（i.p.）接种E.G7肿瘤后，OT - 1细胞在肿瘤部位发生不依赖CD4(+) T细胞的扩增，并产生裂解功能。然而，在肿瘤消除之前，它们离开腹腔（PC）并出现在淋巴结（LN）和脾脏中，在那里它们表现出“分裂失能”，并且不能进一步对抗原增殖。早期给予抗CTLA - 4单克隆抗体导致OT - 1细胞在腹腔内持续扩增，晚期给予则使OT - 1细胞返回腹腔并进一步扩增；在这两种情况下，肿瘤都得到了控制。这些效应需要CD4(+) T细胞和白细胞介素 - 2（IL - 2），并且似乎是由于CD8(+) T细胞无反应状态的逆转所致。