Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13

Abstract

We have previously observed a novel role of natural killer T (NKT) cells in negative regulation of antitumor immune responses against an immunogenic regressor tumor expressing a transfected viral antigen. Here, we investigated whether hidden spontaneous antitumor immunosurveillance, in the absence of a vaccine, could be revealed by disruption of this negative regulatory pathway involving CD4⁺ NKT cells and interleukin-13 (IL-13), in a murine pulmonary metastasis model of a nontransfected, nonregressor, syngeneic tumor, the CT26 colon carcinoma. Lung metastases of CT26 were decreased in CD4⁺ T cell–depleted BALB/c mice, suggesting that CD4⁺ T cells were involved in negative regulation of antitumor responses. CD1-knock out (CD1-KO) mice, which have conventional CD4⁺ T cells and CD4⁺CD25⁺ regulatory T cells but lack CD1-restricted CD4⁺ NKT cells, were significantly resistant to lung metastasis of CT26. The metastases were not further decreased in CD4⁺ T cell–depleted CD1-KO mice, implying that CD4⁺ NKT cells might be the primary negative regulator of antitumor immune responses in BALB/c mice. CD8⁺ T cells were found to act as effectors in antitumor immune responses, since the inhibition of lung metastases observed in naïve CD1-KO or CD4⁺ T cell–depleted mice was abrogated by depletion of CD8⁺ T cells. Lung metastases were significantly decreased by treatment of mice with an IL-13 inhibitor, but not by deficiency or inhibition of IL-4. Thus, even for a nonregressor tumor, immunosurveillance exists but is negatively regulated via CD4⁺ NKT cells possibly mediated by IL-13, and can be unmasked by removal of these negative regulatory components. Published