title: TLR2 ligation protects effector T cells from regulatory T-cell mediated suppression and repolarizes T helper responses following MVA-based cancer immunotherapy.
abstract: Cancer immunotherapy is hampered by the immunosuppression maintained by regulatory T cells (Tregs) in tumor-bearing hosts. Stimulation of the Toll-like receptor 2 (TLR2) by Pam3Cys is known to affect Treg-mediated suppression. We found that Pam3Cys increases the proliferation of both CD4(+) effector T cells (Teffs) and Tregs co-cultured in vitro, but did not induce the proliferation of Tregs alone upon CD3 and CD28 stimulation. In a mouse model of RMA-MUC1 tumors, Pam3Cys was administered either alone or in combination with a modified vaccinia ankara (MVA)-based mucin 1 (MUC1) therapeutic vaccine. The combination of Pam3Cys with MVA-MUC1 (1) diminished splenic Treg/CD4(+) T-cell ratios to those found in tumor-free mice, (2) stimulated a specific anti-MUC1 interferon γ (IFNγ) response and (3) had a significant therapeutic effect on tumor growth and mouse survival. When CD4(+) Teffs and Tregs were isolated from Pam3Cys-treated mice, Teffs had become resistant to Treg-mediated suppression while upregulating the expression of BclL-x(L). Tregs from Pam3Cys-treated mice were fully suppressive for Teffs from naïve mice. Bcl-x(L) was induced by Pam3Cys with different kinetics in Tregs and Teffs. Teff from Pam3Cys-treated mice produced increased levels of Th1 and Th2-type cytokines and an interleukin (IL)-6-dependent secretion of IL-17 was observed in Teff:Treg co-cultures, suggesting that TLR2 stimulation had skewed the immune response toward a Th17 profile. Our results show for the first time that in a tumor-bearing host, TLR2 stimulation with Pam3Cys affects both Tregs and Teffs, protects Teff from Treg-mediated suppression and has strong therapeutic effects when combined with an MVA-based antitumor vaccine.
authors.affiliation: Département d'Immunopharmacologie; Transgene S.A.; Parc d'Innovation; Illkirch-Graffenstaden, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Amiset
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.forename: Tania
authors.initials: T
authors.lastname: Gatard-Scheikl
authors.forename: Karola
authors.initials: K
authors.lastname: Rittner
authors.forename: Vanessa
authors.initials: V
authors.lastname: Duong
authors.forename: Ronald
authors.initials: R
authors.lastname: Rooke
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
authors.forename: Hélène
authors.initials: H
authors.lastname: Haegel