CD11b+Ly6G+ cells inhibit tumor growth by suppressing IL-17 production at early stages of tumorigenesis

Abstract

Neutrophils are important innate immune cells involved in microbial clearance at the sites of infection. However, their role in cancer development is unclear. We hypothesized that neutrophils mediate antitumor effects in early tumorigenesis. To test this, we first studied the cytotoxic effects of neutrophils in vitro. Neutrophils were cytotoxic against tumor cells, with neutrophils isolated from tumor-bearing mice trending to have increased cytotoxic activities. We then injected an ELR+ CXC chemokine-producing tumor cell line into C57BL/6 and Cxcr2−/− mice, the latter lacking the receptors for neutrophil chemokines. We observed increased tumor growth in Cxcr2−/− mice. As expected, tumors from Cxcr2−/− mice contained fewer neutrophils. Surprisingly, these tumors also contained fewer CD8+ T cells, but more IL-17-producing cells. Replenishment of functional neutrophils was correlated with decreased IL-17-producing cells, increased CD8+ T cells, and decreased tumor size in Cxcr2−/− mice, while depletion of neutrophils in C57BL/6 mice showed the opposite effects. Results from a non-ELR+ CXC chemokine producing tumor further supported that functional neutrophils indirectly mediate tumor control by suppressing IL-17A production. We further studied the correlation of IL-17A and CD8+ T cells in vitro. IL-17A suppressed proliferation and IFNγ production of CD8+ T cells, while CD11b+Ly6G+ neutrophils did not suppress CD8+ T cell function. Taken together, these data demonstrate that, while neutrophils could control tumor growth by direct cytotoxic effects, the primary mechanism by which neutrophils exert antitumor effects is to regulate IL-17 production, through which they indirectly promote CD8+ T cell responses.