Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

Abstract

Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1 a , into specific TCR Vb8.1-Tg mice enabled generation of anergic CD25À iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25 À iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25 1 Treg were present, suggesting that depletion of CD25 1 Treg is necessary for p38-inhibitor to be effective. Peptide OVA 323-339 iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25 1 Tregdepletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25 À iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25 1 Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity

“…Without an IL-10 signal, cisplatin-treated DCs did not differentiate into tolerogenic DCs, indicating that induction of tolerogenic DCs by cisplatin requires IL-10 production (Figure 4 and Figure 5). There are several studies showing that p38 MAPK activation in immunosuppressive CD25 − regulatory T cells [38] and tolerogenic DCs [39, 40] is a central pathway to induce IL-10 production. Our finding that cisplatin activates p38 MAPK may explain why cisplatin treatment leads to the generation of IL-10-producing tolerogenic DCs.…”

Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy

“…The immunosuppressive activity of IL-10-producing CD25 -iTreg, but not CD25 ? nTreg, can be selectively blocked by these inhibitors [63]. It has been reported that tumor-associated antigen-specific IL-10-producing iTreg were preferentially induced in patients with metastatic melanoma [64] and CT26-inoculated BALB/c mice [63], suggesting the need to overcome immunotolerance orchestrated by IL-10-producing iTreg.…”

The Mycobacterium tuberculosis Early Secreted Antigenic Target of 6 kDa Inhibits T Cell Interferon-γ Production through the p38 Mitogen-activated Protein Kinase Pathway

“…MAPK is critical for generation of induced Tregs (28) and for Tregs to exhibit suppressor function (29,30). To determine whether the effects of p38 MAPK inhibition observed above were mediated through reducing the capacity of ESAT-6 to enhance Treg function, we studied the effect of ESAT-6 on generation of Tregs by staining for FoxP3 and CD25.…”