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

Gynecol Oncol. 2003 May;89(2):271-80. doi: 10.1016/s0090-8258(03)00083-0.


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 zeta chain and two-color flow cytometric analysis of intracellular cytokine expression (IFN-gamma 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-gamma(high)/IL-4(low)) 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-gamma-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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cytotoxicity, Immunologic / immunology
  • DNA-Binding Proteins*
  • Dendritic Cells / immunology*
  • Female
  • Flow Cytometry
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Membrane Proteins / biosynthesis
  • Oncogene Proteins, Viral / immunology*
  • Papillomavirus E7 Proteins
  • Receptors, Antigen, T-Cell / biosynthesis
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / therapy*


  • DNA-Binding Proteins
  • E7 protein, Human papillomavirus type 18
  • Membrane Proteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain
  • oncogene protein E7, Human papillomavirus type 16
  • Interleukin-4
  • Interferon-gamma