Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration.

Abstract

CD4(+) T cells have been reported to suppress immunity against cancer in certain animal models. In this study, we investigated the role of CD4(+) T cells in the anti-tumor immune response when interleukin-12-producing melanoma cells are inoculated in mice. We found that interleukin-12-transfected B16 melanoma showed retarded tumor growth in syngeneic mice; however, all the mice developed tumors eventually. In vivo depletion of CD4(+) T cells led to complete regression of B16/interleukin-12 tumors in 12 of 20 mice (60%). Immunohistochemical analyses revealed that a number of CD8(+) T cells accumulated in close proximity to the B16/interleukin-12 tumors in the CD4(+) T cell-depleted mice, whereas CD8(+) T cells were only scarcely observed at the periphery of the tumors in control immunocompetent mice. Furthermore, 10 of 20 mice treated with both B16/interleukin-12 inoculation and CD4(+) T cell depletion exhibited vitiligo-like coat color alteration. B16/interleukin-12 tumors completely regressed in all the mice with vitiligo. Histologic examination showed that CD8(+) lymphocytes accumulated around the hair bulbs of mice with vitiligo, but not in those without vitiligo. These results suggest that CD4(+) T cells have an inhibitory effect on tumor rejection by suppressing cytotoxic CD8(+) T cells in this melanoma loading model with local interleukin-12 secretion. To investigate the mechanism of enhanced anti-tumor effects by CD4(+) T cell depletion, we examined the T helper type 1/2 cytokine profile in the tumor draining lymph nodes of B16/interleukin-12-bearing mice with or without CD4(+) T cell depletion using the reverse transcription-polymerase chain reaction method. We found that CD4(+) T cell depletion eliminated T helper type 2 cells and resulted in a T helper type 1-dominant cytokine profile in tumor draining lymph nodes. We emphasize that this T helper type 1-dominant cytokine profile may generate further activated CD8(+) T cells against B16 melanoma cells, lead B16/interleukin-12 to regress, and result in the destruction of the melanocytes in hair bulbs due to cross-antigenicity between both cell types. This mouse model not only demonstrates the depletion of CD4(+) T cells as a useful strategy for cancer gene therapy with interleukin-12 but also provides a model for human melanoma-associated vitiligo.J Invest Dermatol 115:1059-1064 2000

• Authors: H Nagai, I Hara, T Horikawa, M Oka, S Kamidono, M Ichihashi
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 115 Issue 6 Pg. 1059-64 (Dec 2000) ISSN: 0022-202X [Print] United States
• PMID: 11121142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Interleukin-12

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• CD4-Positive T-Lymphocytes (cytology)
• CD8-Positive T-Lymphocytes
• Cytokines (physiology)
• Disease Models, Animal
• Immunoblotting
• Interleukin-12 (metabolism, pharmacology)
• Lymph Nodes (metabolism, pathology)
• Lymphocyte Depletion
• Melanoma, Experimental (drug therapy)
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Reverse Transcriptase Polymerase Chain Reaction
• Th1 Cells (metabolism)
• Th2 Cells (metabolism)
• Transfection
• Vitiligo (etiology)