CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer
Stephan Roux, … , Eric Solary, François Ghiringhelli
Stephan Roux, … , Eric Solary, François Ghiringhelli
Published October 1, 2008
Citation Information: J Clin Invest. 2008;118(11):3751-3761. https://doi.org/10.1172/JCI35890.
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Research Article

CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

Abstract

Tumors that progress do so via their ability to escape the antitumor immune response through several mechanisms, including developing ways to induce the differentiation and/or recruitment of CD4+CD25+ Tregs. The Tregs, in turn, inhibit the cytotoxic function of T cells and NK cells, but whether they have an effect on the cytotoxic function of tumor-infiltrating DCs (TIDCs) has not been determined. Here we have shown, in 2 rodent models of colon cancer, that CD4+CD25+ Tregs inhibit the ability of CD11b+ TIDCs to mediate TNF-related apoptosis-inducing ligand–induced (TRAIL-induced) tumor cell death. In both models of cancer, combination treatment with Mycobacterium bovis Bacillus Calmette-Guérin (BCG), which activates the innate immune system via TLR2, TLR4, and TLR9, and cyclophosphamide (CTX), which depletes Tregs, eradicated the tumors. Further analysis revealed that the treatment led to a marked increase in the number of CD11b+ TIDCs that killed the tumor cells via a TRAIL-dependent mechanism. Furthermore, acquisition of TRAIL expression by the CD11b+ TIDCs was induced by BCG and dependent on signaling through TLR2, TLR4, and TLR9. In vivo transfer of Tregs abrogated the ability of BCG to induce CD11b+ TIDCs to express TRAIL and thereby nullified the efficacy of the CTX-BCG treatment. Our data have therefore delineated what we believe to be a novel mechanism by which Tregs inhibit the antitumor immune response.

Authors

Stephan Roux, Lionel Apetoh, Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Pierre-Emmanuel Puig, Gregoire Lauvau, Laurence Zitvogel, François Martin, Bruno Chauffert, Hideo Yagita, Eric Solary, François Ghiringhelli

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Figure 1

Synergistic antitumor effect of CTX administration followed by intratumoral BCG injections in 2 tumor models.

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Synergistic antitumor effect of CTX administration followed by intratumo...
(A) Four groups of 7 wild-type BD-IX rats received a subcutaneous injection of 1 × 106 syngeneic PROb tumor cells. Rats received 1 i.p. injection of CTX (30 mg/kg) on day 28 after tumor cell injection, or 2 intratumoral injections of BCG (8 × 105 CFU) on day 35 and 42, or both. Control group received saline injections. Statistical comparison of mean tumor volume of the control group and treated groups was performed every 28 days, beginning on day 56. (B) Four groups of 8 wild-type BALB/c mice received a subcutaneous injection of 5 × 105 syngeneic CT26 tumor cells. Mice received 1 i.p. injection of CTX (100 mg/kg body weight) on day 7 after tumor cell injection, or 2 intratumoral injections of BCG (8 × 104 CFU) on day 9 and 14, or both. Untreated mice received saline injections. One experiment out of 3 is shown. Statistical comparison of mean tumor volume of the control group and treated groups was performed on days 15, 20, 25, and 30. *P < 0.05; †P < 0.01. Un, untreated.