PAK1-Dependent Antitumor Effect of AAC-11‒Derived Peptides on Sézary Syndrome Malignant CD4+ T Lymphocytes
| Autor: | Nicolas Thonnart, Jean-Luc Poyet, Ewa Pasquereau-Kotula, Martine Bagot, Justine Habault, Bruno O. Villoutreix, Armand Bensussan, Anne Marie-Cardine |
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| Přispěvatelé: | Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hôpital Robert Debré, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Marie-Cardine, Anne |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cellular immunity [SDV]Life Sciences [q-bio] Clone (cell biology) Dermatology Biochemistry Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Immune system Medicine Molecular Biology Sezary Cell biology business.industry Cell Biology medicine.disease 3. Good health Lymphoma [SDV] Life Sciences [q-bio] 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Antibody business |
| Zdroj: | Journal of Investigative Dermatology Journal of Investigative Dermatology, Nature Publishing Group, 2021, 141 (9), pp.2261-2271.e5. ⟨10.1016/j.jid.2021.01.033⟩ |
| ISSN: | 0022-202X 1523-1747 |
| Popis: | International audience; Sézary syndrome is an aggressive form of cutaneous T-cell lymphoma characterized by the presence of a malignant CD4+ T-cell clone in both blood and skin. Its pathophysiology is still poorly understood, and the development of targeted therapies is hampered by the absence of specific target proteins. AAC-11 plays important roles in cancer cell progression and survival and thus has been considered as an anticancer therapeutic target. In this study, we show that a peptide called RT39, comprising a portion of AAC-11‒binding site to its protein partners coupled to the penetratin sequence, induces the specific elimination of the malignant T-cell clone both ex vivo on the circulating cells of patients with Sézary syndrome and in vivo in a subcutaneous xenograft mouse model. RT39 acts by direct binding to PAK1 that is overexpressed, located in the plasma membrane, and constitutively activated in Sézary cells, resulting in their selective depletion by membranolysis. Along with the absence of toxicity, our preclinical efficacy evidence suggests that RT39 might represent a promising alternative therapeutic tool for Sézary syndrome because it spares the nonmalignant immune cells and, contrary to antibody-based immunotherapies, does not require the mobilization of the cellular immunity that shows heavy deficiencies at advanced stages of the disease. |
| Databáze: | OpenAIRE |
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