Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function.
Tumor growth induced a significant increase of myeloid-derived suppressor cells (MDSCs) in the tumor-bearing host. In our previous study, we showed that MDSCs induced tumor-specific T-cell tolerance and the development of T regulatory cells (Tregs). Tumor-derived factors have been implicated in the accumulation of MDSCs. We hypothesize that reduction of MDSC accumulation in tumor-bearing hosts, through the blockade of tumor factors, can prevent T-cell anergy and Treg development and thereby improve immune therapy for the treatment of advanced tumors. Several tumor-derived factors were identified by gene array analysis. Among the candidate factors, stem- cell factor (SCF) is expressed by various human and murine carcinomas and was selected for further study. Mice bearing tumor cells with SCF siRNA knockdown exhibited significantly reduced MDSC expansion and restored proliferative responses of tumor-infiltrating T cells. More importantly, blockade of SCF receptor (ckit)-SCF interaction by anti-ckit prevented tumor-specific T-cell anergy, Treg development, and tumor angiogenesis. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors. This information supports the notion that modulation of MDSC development may be required to achieve effective immune-enhancing therapy for the treatment of advanced tumors.
Pan
Ping-Ying
PY
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Wang
George X
GX
Yin
Bingjiao
B
Ozao
Junko
J
Ku
Teresa
T
Divino
Celia M
CM
Chen
Shu-Hsia
SH
D019264:Adoptive Transfer; D000818:Animals; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D019089:Stem Cell Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D034741:RNA, Small Interfering; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit