TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune suppressive cells detected in several human cancers. In this study, we investigated the features and immune suppressive function of a novel subset of monocytic MDSC overexpressing TIE-2 (TIE-2+ M-MDSC), the receptor for the pro-angiogenic factor angiopoietin 2 (ANGPT2). We showed that patients with melanoma exhibited a higher circulating rate of TIE-2+ M-MDSCs, especially in advanced stages, as compared to healthy donors. The distribution of the TIE-2+ M-MDSC rate toward the melanoma stage correlated with the serum level of ANGPT2. TIE-2+ M-MDSC from melanoma patients overexpressed immune suppressive molecules such as PD-L1, CD73, TGF-β, and IL-10, suggesting a highly immunosuppressive phenotype. The exposition of these cells to ANGPT2 increased the expression of most of these molecules, mainly Arginase 1. Hence, we observed a profound impairment of melanoma-specific T-cell responses in patients harboring high levels of TIE-2+ M-MDSC along with ANGPT2. This was confirmed by in vitro experiments indicating that the addition of ANGPT2 increased the ability of TIE-2+ M-MDSC to suppress antitumor T-cell function. Furthermore, by using TIE-2 kinase-specific inhibitors such as regorafenib or rebastinib, we demonstrated that an active TIE-2 signaling was required for optimal suppressive activity of these cells after ANGPT2 exposition. Collectively, these results support that TIE-2+ M-MDSC/ANGPT2 axis represents a potential immune escape mechanism in melanoma

Cancer immunotherapy

Tumor cells are recognized by the immune system, which controls the growth of some immunogenic tumors. Cancer immunotherapy is based on the stimulation of this natural defence against cancer. The use of recombinant cytokines (IL-2, IFN!…) and especially of antibodies has demonstrated the clinical efficacy of this approach. New immunotherapeutic strategies are being developed, based on the induction of anti-tumor T lymphocytes by cancer vaccines. The optimization of these vaccines is based on their validation in relevant preclinical and clinical models (spontaneous tumors in rodents and carnivore), on their association withmolecules able to inhibit the resistancemechanisms of tumours to immunotherapy, and on more clearly defined clinical indications.Des cellules tumorales peuvent être reconnues par le système immunitaire qui contrôle le développement de certaines tumeurs. L'immunothérapie anti-tumorale consiste à stimuler cette immunité naturelle contre les cancers. L'emploi de cytokines recombinantes (IL-2, IFNα...) et surtout d'anticorps a permis de démontrer l'efficacité clinique de cette approche. De nouvelles stratégies d'immunothérapie reposant sur l'induction de lymphocytes T anti-tumoraux par des vaccins sont en cours de développement. L'optimisation de ces vaccins repose sur leur validation dans des modèles cliniques pertinents (tumeurs spontanées des rongeurs et des carnivores), sur leur association à des molécules permettant de lever des mécanismes de résistance de la tumeur à l'immunothérapie et sur des indications cliniques mieux définies de ces vaccins

Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators

Identification de peptides immunogènes dérivés de la télomérase et optimisation de l'utilisation de la sous-unité B de la toxine de Shiga comme vecteur vaccinal

Dans une première partie, nous avons utilisé une approche prédictive pour identifier des épitopes T CD8+ immunogènes dérivés de la télomérase et restreints par l allèle HLA-B7. Les peptides identifiés ont été validés in vivo chez des souris transgéniques pour HLA-B7, et in vitro chez des donneurs sains et des patients atteints de cancer. Des lignées CTL spécifiques de certains peptides sont capables de lyser des cellules tumorales surexprimant la télomérase. Dans une deuxième partie, nous avons analysé le mécanisme d action in vivo d un vecteur vaccinal non réplicatif, la sous-unité B de la toxine de Shiga (STxB). Ainsi, STxB couplée à un antigène cible préférentiellement les cellules dendritiques myéloïdes (CD11c+CD8 ), et induit une réponse LT CD8+ efficace. La combinaison de l alpha-galactosylceramide avec STxB permet d optimiser l efficacité de ce vecteur, de rompre une tolérance contre un antigène du soi, d induire une immunité antivirale et antitumorale protectrices.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Is preexisting antitumor CD4 T cell response indispensable for the chemotherapy induced immune regression of cancer?

International audienceInsights into antitumor T-cell responses may help the development of more efficient treatments for lung cancer. The interplay between preexisting antitumor CD4(+) T-cell responses and platinum-based chemotherapy is crucial to improve patient survival. Accumulating evidence confirms that selecting cancer patients in whom chemotherapy can activate an anticancer immune response would largely improve the success of novel therapeutic approaches

L’immunité adaptative : activation et polarisation des lymphocytes T. Chapitre 11

International audienc

L’immunité adaptative : activation et polarisation des lymphocytes T. Chapitre 11

International audienc

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials

L’immunité adaptative : activation et polarisation des lymphocytes T. Chapitre 11

International audienc