Intégration de l’analyse de l’immunomodulation induite par les inhibiteurs de mTOR dans leur développement en cancérologie

Abstract : The key role of the mTOR (mammalian Target of Rapamycin) pathway in cellular homeostasis raises a real interest in many therapeutics areas. Inhibitors of mTOR (mTORi) are used for graft rejection prevention to inhibit the T lymphocyte (LT) activation and induce regulatory T cells (LTreg). In cancerology, they are used for their antiproliferative and antiangiogenic actions. However, the clinical efficacy of those treatments is low. Although several mTORi resistance mechanisms linked to the tumor cell have been identified, their impact on the immune system appears as a key factor in their efficiency. Thus, our hypothesis is that the clinical efficacy of mTORi could also be dependent of an anti-tumoral immunity modulation resulting from those treatments.We performed an immunomonitoring of the Treg rate and the tumor specific Th1 anti-tumor response among a prospective cohort of patients with a metastatic renal carcinoma treated by everolimus (mTORi). We observed that the Treg rate and the suppressive function increase after the second month of treatment for almost all the patients. Paradoxically, an increase of the Th1 anti-tumoral response has also been observed for these patients. At disease progression, a majority of the patients has shown an important increase of Treg with a decrease of the Th1 response. Thus, we have been able to define different immune profiles based on the modulation of these two parameters. Progression free survival of patients with an earlier decrease of Treg and an increase of Th1 response was significantly longer compared to other patients (13.2 vs 4 months p=0.02). This immunomodulation has been consistently confirmed with patients affected by neuroendocrine tumor and treated with everolimus. The treatment impact on Treg and the Th1 response was not related to the pharmacokinetic of the drug. Thereafter, we have studied in vivo the impact of mTORi on the anti-tumoral immune response with mice affected by different tumors. We have observed the same increase of Treg in mice treated with mTORi as the increase observed in the patients. Thus, using antibodies depleting the Treg or transgenic mice allowed us to confirm the deleterious role of Treg on the anti-tumor mTORi efficacy. Those results strongly suggest that mTORi have a double effect on the immune system, a harmful impact by the induction of an immunosuppressive environment and a positive impact by the increase of the anti-tumor Th1 response.In a second time, we have studied the positive effect of mTORi on the immune system in order to optimize the anti-tumoral immunotherapies. We have shown that the administration of temsirolimus (mTORi) improves the anti-tumoral efficiency of a therapeutic vaccination on mice. Indeed, the synergic effect of this combination is tied with an augmentation of tumor infiltrate anti-tumor T CD8 with a central memory phenotype. The efficiency of this combination has been greatly improved by the addition of an antagonist CCR4 allowing the elimination of Treg generated by temsirolimus.In conclusion, mTORi remain a promising strategy in cancerology even if their use is likely to be reduced as new immunotherapies such as checkpoint inhibitors (renal carcinoma) or other targeted therapies (cycline dependent kinase inhibitors in breast cancer) appeared. In the future, the development of mTORi must integrate biomarkers taking into account the impact of these treatments on the immune system, and therapeutic combination such as the immunotherapy
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Laura Mansi. Intégration de l’analyse de l’immunomodulation induite par les inhibiteurs de mTOR dans leur développement en cancérologie. Médecine humaine et pathologie. Université Bourgogne Franche-Comté, 2017. Français. ⟨NNT : 2017UBFCE012⟩. ⟨tel-02108081⟩

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