Faculty Collaboration Database

Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo. J Immunol 2008 Aug 01;181(3):1877-86

Date

07/22/2008

Pubmed ID

18641325

Pubmed Central ID

PMC3804024

DOI

10.4049/jimmunol.181.3.1877

Scopus ID

2-s2.0-49649104777 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

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.

Author List

Zhou Q, Yan X, Gershan J, Orentas RJ, Johnson BD

Author

Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Annexin A5
Cancer Vaccines
Cell Proliferation
Cells, Cultured
Gene Expression Regulation
Macrophage Migration-Inhibitory Factors
Mice
Neoplasm Transplantation
Neuroblastoma
Protein Binding
RNA Interference
T-Lymphocytes