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.