Increased expression of IL-21 reduces tumor growth by modulating the status of tumor-infiltrated lymphocytes

The role of interleukin (IL)-21 in influencing tumor growth or enhancing anti-tumor immunity is somewhat controversial. To further understand the potential regulatory effects of IL-21, we utilized an IL-21-secreting EG7 tumor model to demonstrate the direct effects of IL-21 on host tumor-infiltrating lymphocyte (TIL) profiles. Vector control EG7 cells (EG7-Vec) produced very low amounts of IL-21 and were highly tumorigenic. In contrast, IL-21-expressing EG7 cells, EG7-IL-21L and EG7-IL-21H, secreted relatively and extremely high levels of IL-21, respectively. Most importantly, both IL-21-expressing EG7 cells' control of tumor growth was not due to increased proliferative ability of tumor cells, but resulted from the induction of cytotoxic cellular responses in immunocompetent mice. To identify the effects of cancer immunoediting, tumor-infiltrating lymphocyte profiles were analyzed. NK cell populations appeared to be increased in EG7-IL-21H tumor sites at days 6-8 (progression stage), though this phenomenon did not persist at days 10-12 (regression stage). However, at both days 6-8 and 10-12, a higher frequency of CD8⁺ T cells was observed at the tumor site in EG7-IL-21H-inoculated mice than in EG7-Vec-inoculated mice. These findings suggest that NK cell-mediated tumor rejection may efficiently drive the development of tumor-specific cytotoxic T cell responses with the help of elevated IL-21 expression. These results also suggest the therapeutic potential of IL-21.