title: In vivo depletion of T lymphocyte-specific transcription factors by RNA interference.
abstract: The generation of specific T lymphocyte subsets is under the strict control of specific transcription factors, as this has been shown by knockout experiments in mice. Here, we show that siRNAs that specifically target the transcription factor Gata3 (which is required for the development of T helper 1 cells) or T-Bet (which is required for the development of T helper 2 cells) can be effective in vivo. Thus, the intraperitoneal injection of siRNAs specific for Gata3 or t-Bet leads to the specific depletion of their target gene products in vivo, in the spleen and in the lymph nodes of mice. The immunomodulatory action of these siRNAs was validated in a model of anti-tumor vaccination in which colorectal cancer cells that succumb to anthracyclin-induced immunogenic cell death were injected subcutaneously into one flank, in the absence of any adjuvant and live tumor cells were injected simultaneously in the opposite flank of immunocompetent mice. In this setting, the siRNA targeting t-Bet was able to accelerate tumor growth while the siRNA targeting Gata3 significantly reduced the proliferation of cancer cells in vivo. These effects were dependent on the immune response elicited by dying tumor cells because both siRNAs failed to modulate the growth of tumors in non-vaccinated mice. The immune response-dependent anticancer effect of the Gata3-specific siRNA was not due to the induction of class I interferons and could be fully abolished by co-injection of t-Bet-specific siRNA. These results demonstrate the possibility to use siRNAs for immunomodulaton in vivo and illustrate the antagonistic implication of distinct T helper populations in anti-cancer immune responses.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: Nassera
authors.initials: N
authors.lastname: Abermil
authors.forename: Frederic
authors.initials: F
authors.lastname: Schlemmer
authors.forename: Noelia
authors.initials: N
authors.lastname: Casares
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Marie
authors.initials: M
authors.lastname: Pequignot
authors.forename: Mickael
authors.initials: M
authors.lastname: Michaud
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martins
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050990:GATA3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D034741:RNA, Small Interfering