Antigen-driven Selection and Long-Term Persistence Human Renal Cell Carcinoma Antigen-specific CTLs:

Renal cell carcinomas (RCCs) are thought to be immunogenic, because cytokine-induced and even spontaneous tumor regression has been ob served in a significant number of patients. However, little is known about the nature of immune responses that might lead to tumor regression. We studied naturally arising human T-cell responses against RCC by com bining molecular analyses of T-cell receptor (TCR) usage in primary tumors in situ with functional analyses of tumor-infiltrating lymphocytes (TILs) in vitro. TILs of patient 26 that were cultured in vitro showed a human leukocyte antigen (HLA-A*0201)-restricted cytotoxic activity spe cific for autologous tumor cells. These tumor-derived lymphocytes were dominated by a family of T cells expressing Va20and Vß22-positive TCRs. Their specificity-conferring third complementarity-determining regions were highly homologous with respect to the loop length and selection of particular amino acids in both TCR chains. These character istics are similar to those reported for antigen-selected murine T cells recognizing immunodominant epitopes of non-self proteins. To evaluate the biological significance of these CTLs in vivo, we analyzed the corre sponding TCR transcripts in the cryopreserved tumor material of patient 26 and in a second HLA-A*0201-positive RCC patient whose tumor cells were also lysed by TIL-26. The in situ TIL populations of both patients used related families of highly homologous TCRs, supporting the conten tion that immunodominant responses directed against a shared tumorassociated antigen occurred in both individuals in vivo. Furthermore, in the absence of overt metastatic disease, the tumor antigen-specific CTLs of patient 26 were shown to persist in the periphery 4 years after removal of the primary tumor. These results demonstrate that antigen-driven T-cell responses specific for spontaneously arising carcinomas developed in these patients and showed long-term persistence, even in the absence of iinniiinotherapy.