Induction of human papillomavirus-specific CD4(+) and CD8(+) lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16-and 18-positive cervical cancer

Human papillomavirus (RPV) type 16 (HPV 16) and HPV type 18 (HPV 18) are im plicated in the induction and progression of the majority of cervical cance rs. Since the E6 and E7 oncoproteins of these viruses are expressed in thes e lesions, such proteins might be potential tumor-specific targets for immu notherapy. In this report, we demonstrate that recombinant, full-length E7- pulsed autologous dendritic cells (DC) can elicit a specific CD8(+) cytotox ic T-lymphocyte (CTL) response against autologous tumor target cells in thr ee patients with HPV 16- or HPV 18-positive cervical cancer. E7-specific CT L populations expressed strong cytolytic activity against autologous tumor cells, did not lyse autologous concanavalin A-treated lymphoblasts or autol ogous Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL), and s howed low levels of cytotoxicity against natural killer cell-sensitive K562 cells. Cytotoxicity against autologous tumor cells could be significantly blocked by anti-HLA class I (W6/32) and anti-CD11a/LFA-1 antibodies. Phenot ypically, all CTL populations were CD3(+)/CD8(+), with variable levels of C D56 expression. CTL induced by E7-pulsed De were also highly cytotoxic agai nst an allogeneic HLA-A2(+) HPV 16-positive matched cell line (CaSki). In a ddition, we show that specific lymphoproliferative responses by autologous CD4(+) T cells can also be induced by E7-pulsed autologus DC. E7-specific C D4+ T cells proliferated in response to E7-pulsed LCL but not unpulsed LCL, and this response could be blocked by anti-HLA class II antibody. Finally, with two-color flow cytometric analysis of intracellular cytokine expressi on at the single-cell level, a marked Th1-like bias las determined by the f requency of gamma interferon- and interleukin 4-expressing cells) was obser vable for both CD8(+) and CD4(+) E7-specific lymphocyte populations. Taken together, these data demonstrate that full-length E7-pulsed DC can induce b oth E7-specific CD4(+) T-cell proliferative responses and strong CD8(+) CTL responses capable of lysing autologous naturally HPV-infected cancer cells in patients with cervical cancer. These results may have important implica tions for the treatment of cervical cancer patients with active or adoptive immunotherapy.