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Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4⁺CD25^high Regulatory T Cell Function In Vivo¹

Josianne Nitcheu-Tefit^*, Ming-Shen Dai^*,, Rebecca J. Critchley-Thorne^2,*, Francisco Ramirez-Jimenez, Man Xu^*,, Sophie Conchon^¶,||, Nicolas Ferry^¶,||, Hans J. Stauss and Georges Vassaux^3,*,¶,||

^* Centre for Molecular Oncology, Institute of Cancer, Queen Mary’s School of Medicine and Dentistry, London, United Kingdom; Department of Immunology and Molecular Pathology, Royal Free Hospital, London, United Kingdom; Department of Pathology, Chongqing University of Medical Sciences, Chongqing, China; Division of Haematology/Oncology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan; ^¶ Institut National de la Santé et de la Recherche Médicale Centre d’Investigation Clinique-04, Universite de Nantes, Nantes Atlantique Universites, Centre Hospitalier de l’Université (CHU) Hotel Dieu, Nantes, France; and ^|| Institut des Maladies de l’Appareil Digestif, CHU Hotel Dieu, Nantes, France

CD4⁺CD25^high regulatory T cells (Treg) protect the host from autoimmune diseases but are also obstacles against cancer therapies. An ideal cancer vaccine would stimulate specific cytotoxic responses and reduce/suppress Treg function. In this study, we showed that Escherichia coli expressing listeriolysin O and OVA (E. coli LLO/OVA) demonstrated remarkable levels of protection against OVA-expressing tumor cells. By contrast, E. coli expressing OVA only (E. coli OVA) showed poor protection. High-avidity OVA-specific CTL were induced in E. coli LLO/OVA-vaccinated mice, and CD8⁺ depletion—but not NK cell depletion, abolished the antitumor activity of the E. coli LLO/OVA vaccine. Phenotypic analysis of T cells following vaccination with either vaccine revealed preferential generation of CD44^highCD62L^low CD8⁺ effector memory T cells over CD44^highCD62L^high central memory T cells. Unexpectedly, CD4⁺ depletion turned E. coli OVA into a vaccine as effective as E. coli LLO/OVA suggesting that a subset of CD4⁺ cells suppressed the CD8⁺ T cell-mediated antitumor response. Further depletion experiments demonstrated that these suppressive cells consisted of CD4⁺CD25^high regulatory T cells. We therefore assessed these vaccines for Treg function and found that although CD4⁺CD25^high expansion and Foxp3 expression within this population was similar in all groups of mice, Treg cells from E. coli LLO/OVA-vaccinated animals were unable to suppress conventional T cells proliferation. These findings provide the first evidence that LLO expression affects Treg cell function and may have important implications for enhancing antitumor vaccination strategies in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Cancer Research U.K., the Medical Research Council, Institut National de la Santé et de la Recherche Médicale (INSERM), and by Grant 0607-3D1615-66/AO INSERM from the French National Cancer Institute (INCa).

² Current address: Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305.

³ Address correspondence and reprint requests to Dr. Georges Vassaux, Institut National de la Santé et de la Recherche Médicale CIC-04, EE 0502, 3ème étage HNB nord, Centre Hospitalier de l’Université Hotel Dieu, 1 place Alexis Ricordeau, 44035 Nantes Cedex 1, France. E-mail address: georges.vassaux{at}nantes.inserm.fr

⁴ Abbreviations used in this paper: LLO, listeriolysin O; DC, dendritic cell; BMDC, bone marrow-derived DC; LN, lymph node; Treg, regulatory T; T_EM, effector memory T; T_CM, central memory T; T_CONV, conventional T.