Epstein-Barr virus-induced gene 3-deficiency leads to impaired antitumor T-cell responses and accelerated tumor growth

Abstract

Epstein-Barr virus-induced gene 3 (EBI3) encoded protein can form heterodimers with IL-27P28, and IL-12P35 to form IL-27, and IL-35. However, IL-27 stimulates, whereas IL-35 inhibits antitumor T-cell responses. IL-27 also limits the Foxp3⁺ regulatory T cell (Treg) population, whereas IL-35 has been shown to expand Tregs and foster Treg suppressive functions. It remains unclear which group of forces are dominant during antitumor T-cell responses. In this study, we evaluated the tumor growth and antitumor T-cell responses in EBI3-deficient mice that lack both IL-27 and IL-35. We found that injecting B16 melanoma cells into EBI3-deficient C57BL/6 mice, or J558 plasmacytoma cells into EBI3-deficient BALB/c mice resulted in significantly increased tumor growth relative to those implanted in wild-type control mice. Tumors from EBI3-deficient mice contained significantly decreased proportions of CD8⁺ T cells and increased proportions of CD4⁺FoxP3⁺ Treg cells as compared to those from EBI3-intact mice. Tumor-infiltrating T cells from EBI3-deficient mice were impaired in their capacity to produce IFNγ. Phenotypically, Tregs from EBI3-deficient mice were highly suppressive and produced IL-10 in the tumor microenvironment. Depletion of Tregs or inactivation of the IL-10 pathway significantly abrogated tumor growth enhancement in Ebi3^−/− mice. Finally, we showed that Ebi3^−/− mice administered a melanoma vaccine failed to mount a CD8⁺ T-cell response and the vaccine failed to confer tumor rejection in EBI3-deficient mice. Taken together, these results suggest that Ebi3^−/− mice show a phenotype of IL-27-deficiency rather than IL-35-deficiency during anti-tumor T-cell responses. Thus, our results suggest that endogenous IL-27 is critical for both spontaneous and vaccine-induced antitumor T-cell responses.

Keywords:

• Epstein-Barr virus-induced gene 3
• IL-27
• IL-35
• Treg
• tumor immunity

Abbreviations:

• APC, antigen-presenting cells; CTL, cytotoxic T lymphocyte; EBI3, Epstein-Barr virus-induced gene 3; Th, T helper; Treg, regulatory T cells.

Disclosure of Potential Conflicts of Interest

The authors declare no financial or commercial conflict of interest.

Acknowledgment

This study is supported by grants from the National Cancer Institute (R01CA138427 to XFB) and American Cancer Society (RSG-09-188-01-LIB to XFB).