Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix.
(2003) Gynecologic Oncology —
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- Objective: To evaluate the potential of autologous dendritic cells (DC) pulsed with HPV16 and HPV18 E7 oncoprotein in restoring tumor-specific cytotoxicity in populations of tumor infiltrating lymphocytes (TIL) for adoptive immunotherapy of cervical cancer patients. Methods: Full-length E7-pulsed DC-stimulated CD8+ T cells derived from peripheral blood (PBL) and from tumor tissues (TIL) were tested and compared for their ability to induce a HLA class-I-restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. In addition, in order to correlate cytotoxic activity by CTL with a particular lymphoid subset, analysis of surface antigens and intracellular CD3 ζ chain and two-color flow cytometric analysis of intracellular cytokine expression (IFN-γ vs IL-4) at the single cell level were performed. Results: DC stimulation induced powerful cytotoxicity against autologous tumor target cells by TIL-derived CD8+ T cells from all three cervical cancer patients, while autologous Epstein–Barr virus-transformed lymphoblastoid cell lines were not lysed. Killing of autologous tumor cells was higher by CD8+ T cells from TIL compared to PBL (P > 0.01) and was more strongly inhibited by anti-HLA class I MAb (P > 0.05). Phenotypically, all CTL populations were CD3+/CD8+, with higher levels of CD56 expression by TIL-derived CTL. Finally, although a marked Type 1 cytokine bias (i.e., IFN-γhigh/IL-4low) was observable in both PBL- and TIL-derived DC-stimulated CD8+ T cell populations, TIL-derived CD8+ T cells showed a higher percentage of IFN-γ-positive cells compared to PBL. Conclusions: Full-length E7-pulsed DC can consistently restore strong CD8+ CTL responses against autologous HPV16- and HPV18-infected cervical cancer cells. DC-stimulated TIL may represent a superior source of tumor-specific CTL compared to PBL for adoptive T cell immunotherapy of patients harboring metastatic or recurrent cervical cancer refractory to standard treatment modalities.
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Santin, A. D., Bellone, S., Palmieri, M., Bossini, B., Roman, J. J., Cannon, M. J., Bignotti, E., Cané, S., & Pecorelli, S. (2003). Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecologic Oncology. https://doi.org/10.1016/S0090-8258(03)00083-0