Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo.
Neuroblastomas and many other solid tumors produce high amounts of macrophage migration inhibitory factor (MIF), which appears to play a role in tumor progression. We found that MIF expression in neuroblastoma inhibits T cell proliferation in vitro, raising the possibility that MIF promotes tumorigenesis, in part, by suppressing antitumor immunity. To examine whether tumor-derived MIF leads to suppression of T cell immunity in vivo, we generated MIF-deficient neuroblastoma cell lines using short hairpin small interfering RNAs (siRNA). The MIF knockdown (MIFKD) AGN2a neuroblastoma cells were more effectively rejected in immune-competent mice than control siRNA-transduced or wild-type AGN2a. However, the increased rejection of MIFKD AGN2a was not observed in T cell-depleted mice. MIFKD tumors had increased infiltration of CD8(+) and CD4(+) T cells, as well as increased numbers of macrophages, dendritic cells, and B cells. Immunization with MIFKD AGN2a cells significantly increased protection against tumor challenge as compared with immunization with wild-type AGN2a, and the increased protection correlated with elevated frequencies of tumor-reactive CD8(+) T cells in the lymphoid tissue of treated animals. Increased numbers of infiltrating tumor-reactive CD8(+) T cells were also observed at the site of tumor vaccination. In vitro, treatment of AGN2a-derived culture supernatants with neutralizing MIF-specific Ab failed to reverse T cell suppressive activity, suggesting that MIF is not directly responsible for the immune suppression in vivo. This supports a model whereby MIF expression in neuroblastoma initiates a pathway that leads to the suppression of T cell immunity in vivo.
Zhou
Qiang
Q
Department of Pediatrics, Medical College of Wisconsin, and the Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
Yan
Xiaocai
X
Gershan
Jill
J
Orentas
Rimas J
RJ
Johnson
Bryon D
BD
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D017304:Annexin A5; D019496:Cancer Vaccines; D008263:Macrophage Migration-Inhibitory Factors