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Yin Yang of immunoregulation in organ transplantation and cancer The ‘Yin Yang of Immunoregulation: Cancer and Organ Transplantation’ meeting took place in Nantes, France on 2–3 December 2010 and was dedicated to the biology of myeloid and lymphoid immune cells in the context of cancer and transplantation. This meeting was organized by the Immunotherapy Research group of the Western France Cancer Network Cancéropole Grand-Ouest and the Immunomonitorage et Biothérapies network (IMBIO) research program, which is supported by the Région Pays de la Loire. Immunoregulation can be defined as the physiological mechanisms involved in the regulation of the different phases of an immune response (initiation, activation, effectorphase and suppression). Immunoregulation thus plays a pivotal role in the maintenance of immune homeostasis. During recent years, studies have underlined the complexity of the cellular and molecular mechanisms of immunoregulation. The role played by immunoregulation was clearly evidenced in autoimmune diseases and chronic inflammation, which are associated with an inappropriate or dysregulated/unabated immune response directed against self components. The role of immunoregulation was also evidenced in other physiopathological situations where the immune system can be repressed or diverted, such as in cancer. Indeed, the tumor site and draining lymph nodes contain immuno suppressive mediators (such as IL-10 and TGF‑b) and are infiltrated by immunosuppressive cells, such as natural or inducible regulatory T cells (Tregs) and myeloid cells, such as tumorassociated macrophages, dendritic cells and neutrophils, that may affect the effector functions of effector cells. These observations led to the hypothesis that manipulating the immunoregulation network may represent an original and potent alternative therapeutic approach for the treatment of severe immune-related diseases, such as cancer and transplant rejection. The rationale of this meeting, organized by immunologists specialized in immuno–oncology and transplantation, was driven by the notion that clinicians and scientists working on immunoregulation in apparently opposite fields, cancer and transplantation, may benefit from cross-discussions on their hypothesis,
favorite targets, therapeutic strategies and preclinical models. For this first meeting, the organizers focused on the cellular side of immunoregulation. Four sessions were dedicated to the most important players of immunoregulation, dendritic cells, macrophages, Tregs and myeloid-derived suppressive cells. After a special opening session by Jacques Banchereau (Baylor Institute for Immunology Research, TX, USA), each session included two main talks, given by an international renowned scientist and a scientist from western France, followed by short oral communications by invited speakers. During the first session on tolerogenic dendritic cells, Rosa Bacchetta (San Raffaele Scientific Institute, Milan, Italy) presented data on the ways to generate Tr1 cells and their use in allogenic transplantation. She demonstrated that exogenous IL-10 or IL-10 produced by tolerogenic dendritic cells induces in vitro the generation of alloantigen-specific Tr1 cells suitable for cell therapy. Finally, Bacchetta presented results from clinical studies showing that donor T cells anergized in vitro in the presence of IL-10 provide immunoreconstitution associated, in most of the patients, with only moderate graft-versus-host disease. The presentation by Alexis Kalergis (INSERM U643, Nantes, France) was dedicated to the molecular interactions occurring between antigen-presenting cells and T cells at the immunological synapse, and underlined their role in the regulation of the adaptive immune response, as disturbed antigen-presenting cell–T-cell signaling could be detrimental for the host, either due to an insufficient immune response or to autoreactivity. Kalergis presented ways of setting up new therapies directed to treat autoimmune disorders by manipulating the immune
Yves Delneste†1,2,3, Marc Gregoire1,4, Mari Cristina Cuturi1,4,5 & Ignacio Anegon1,4,5
10.2217/IMT.11.54 © 2011 Future Medicine Ltd
Immunotherapy (2011) 3(4 Suppl. 1), 1–3
ISSN 1750-743X
INSERM, U892, Centre de Recherche sur le Cancer Nantes-Angers, F-49933 Angers, France 2 Université d’Angers, UMR-S892, F-49933 Angers, France 3 CHU d’Angers, Laboratoire d’Immunologie et Allergologie, F-49933 Angers, France 4 Université de Nantes, UMR-S892, F-44000 Nantes, France 5 CHU de Nantes, Institut de Transplantation et de Recherche en Transplantation, F-44000 Nantes, France † Author for correspondence: Tel.: +33 244 688 300
[email protected] 1
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Foreword
Delneste, Gregoire, Cuturi & Anegon
synapse. This first session also included presentations on the role of carbon monoxide in the generation of tolerogenic CD8 + T cells (Philippe Blancou, ONIRIS, Nantes, France) and the role of regulatory B cells in controlling dendritic cell functions (Richard Lo-Man, Pasteur Institute, Paris, France). The second session was dedicated to macro phages. The first presentation by Alberto Mantovani (Istituto Clinico Humanitas, Milan, Italy) focused on the mechanisms involved in the generation of tumor-associated macrophages (TAMs) and the in vitro generation of macrophage subsets exhibiting stimulatory (M1) or regulatory (M2) properties. Mantovani also presented an overview on the role of innate immunity in the initiation, polarization and regulation of the adaptive immune responses, as exemplified with the soluble pattern recognition receptor pentraxin 3. Pascale Jeannin (INSERM Unit 892, Angers, France) presented data demonstrating that two members of the IL-6 family, IL-6 and LIF, are involved in the generation of TAMs in ovarian cancer. Jeannin also presented data showing that, in vitro, IL-6 and LIF induce the differentiation of monocytes into macrophages that are phenotypically and functionally similar to TAMs. Finally, in a therapeutic perspective, Jeannin showed that IFN-g not only prevented the differentiation of monocytes into TAM-like cells, but also reverted TAM into immunostimulatory M1 macrophages. This second session ended with presentations on the privileged status of the CNS immune system. Philippe Naveilhan (INSERM Unit 643, Nantes, France) presented data on the immunoregulatory role of neural stem cells and Tony Avril (Biology Deptartment, Centre Eugène Marquis, Rennes, France) presented data on the mechanisms of i mmunomodulation in human glioblastoma. The third session focused on Tregs. Giovanna Lombardi (MRC Center for Transplantation, King’s College, London, UK) spoke of skin transplant tolerance induced by Treg cells generated by targeting in vivo quiescent dendritic cells with alloantigen in a murine model. In a therapeutic perspective in humans, Lombardi presented the generation and characterization of alloantigen-specific Tregs at a clinical grade and showed that these alloantigen-specific Tregs are more efficient than polyclonal ones in protecting from CD4 + T-cell-mediated pathology in a human skin transplant model in immunodeficient mice. 2
Immunotherapy (2011) 3(4 Suppl. 1)
Maya Ayyoub (INSERM Unit 892, Nantes, France) presented a complete overview on the current knowledge of CD4 + T-cell subsets (Th1, Th2, Th17 and Treg), showing that the mechanisms involved in their generation are more complicated than recently thought as these cells are functionally plastic and may differentiate into each other when receiving appropriate signals. Ayyoub presented data on the identification of a subpopulation of memory Tregs that secrete IL-17 ex vivo and constitutively express RORgt, a molecule commonly recognized as a Treg-‘specific’ marker. This session also included two short presentations on the characterization of CD8 + Treg T-cell receptor–MHC interaction in allotransplantation by Caroline Guilloneau (INSERM Unit 643, Nantes, France) and on the role of Tregs in the in vivo growth of hepatocellular carcinoma in mice by Sophie Conchon (INSERM Unit 948, Nantes, France). The fourth session was dedicated to myeloid-derived suppressor cells. The first talk by Mario Colombo (Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy) presented original data on the unexpected role of mast cells in regulating tumor growth and their inter action with Tregs and matricellular components. Bernard Vanhove (INSERM Unit 643, Nantes, France) gave an overview on the phenotype and functional characteristics of myeloid-derived suppressor cells and their potential beneficial role to suppress unwanted immune responses, such as in allograft rejection. Vanhove also presented data on the role of myeloid-derived suppressor cells in regulating innate and adaptive immunity. This session ended with a short oral presentation by Marcelo Hill (INSERM Unit 643, Nantes, France) on the role of the molecule Tmem167b in controlling antigen cross-presentation. A selection of short articles and abstracts are included in this supplement issue of Immunotherapy.
Conclusion As organizers, we were happy to see that the presentations by invited speakers stimulated many discussions, especially during the final round table. The informal environment, in which breaks and meals were particularly appreciated, allowed establishing many contacts between scientists. These are very encouraging aspects for the organization of a forthcoming second edition on immunoregulation in western France. future science group
Yin Yang of immunoregulation in organ transplantation & cancer
Acknowledgements We thank Sylvene Renoud, Anne Kerdrael, and Matthieu Crapart (Canceropole Grand Ouest, Nantes, France), for their invaluable assistance.
Financial & competing interests disclosure The organization of this meeting would not have been possible without support from the Canceropole Grand Ouest
future science group
Foreword
(www.canceropole-grandouest.com) and Région Pays de la Loire – IMBIO network (www.imbio.fr). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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