Identificação de um novo alvo terapêutico contra a leucemia de linfócitos T

Com a importante colaboração de equipas de investigação francesas, o investigador Nuno Rodrigues dos Santos, atualmente afiliado no Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), descobriu que a estimulação de um recetor específico dos linfócitos T (TCR) levava à morte de células de leucemia de linfócitos T, uma doença maligna que afeta maioritariamente crianças e adolescentes, mas também adultos. Esta descoberta surgiu com o estudo de murganhos com leucemia, no Centro de Investigação em Biomedicina da Universidade do Algarve, onde se verificou que a estimulação do TCR através de um antigénio ou da inoculação de um anticorpo específico curava ou prolongava o tempo de vida dos murganhos com leucemia. Estes resultados foram posteriormente confirmados pelos colaboradores em França, tratando com anticorpo murganhos transplantados com leucemias humanas. Assim, estas descobertas demonstram que o tratamento com um anticorpo estimulador do TCR pode vir a ser uma nova terapia contra a leucemia de linfócitos T.

Autores e Afiliações:

Amélie Trinquand¹, Nuno R. dos Santos^2,3, Christine Tran Quang^3,4, Francesca Rocchetti^3,4, Benedetta Zaniboni^3,4, Mohamed Belhocine^1,5, Cindy Da Costa de Jesus^3,4, Ludovic Lhermitte¹, Melania Tesio¹, Michael Dussiot⁶, François-Loïc Cosset⁷, Els Verhoeyen^7,8, Françoise Pflumio⁹, Norbert Ifrah¹⁰, Hervé Dombret¹¹, Salvatore Spicuglia⁵, Lucienne Chatenoud¹², David-Alexandre Gross¹², Olivier Hermine ^6,13, Elizabeth Macintyre¹, Jacques Ghysdael^3,4,* and Vahid Asnafi¹,*

¹ Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.

² Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.

³ Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France.

⁴ Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France.

⁵ Technological Advances for Genomics and Clinics (TAGC), INSERM U1090, Université de la Méditerranée, Marseille, France.

⁶ INSERM UMR 1163 and CNRS ERL 8654, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Laboratory of Excellence GR-Ex, Imagine Institute and Paris Descartes University, Sorbonne Paris Cité, Paris, France.

⁷ CIRI, EVIR Team, INSERM U1111, CNRS UMR 5308, Université de Lyon-1, ENS de Lyon, Lyon, France.

⁸ INSERM U1065, C3M, Equipe “Contrôle Métabolique des Morts Cellulaires,” Nice, France.

⁹ Laboratoire des Cellules Souches Hématopoïétiques et Leucémiques, UMR 967, INSERM, Commissariat à l'Energie Atomique, Université Paris Diderot, Université Paris 11, Institut de Radiobiologie Cellulaire et Moléculaire, équipe labellisée Ligue Nationale contre le Cancer, Fontenay-aux-Roses, France.

¹⁰ PRES LUNAM, CHU Angers service des Maladies du Sang et INSERM U892, Angers, France.

¹¹ Université Paris 7, Hôpital Saint-Louis, AP-HP, Department of Hematology and Institut Universitaire d'Hématologie, Paris, France.

¹² Institut Necker Enfants Malades, INSERM U1151, CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France, and Université Paris Descartes Sorbonne Paris Cité, Paris, France.

¹³ Department of Clinical Hematology, Hôpital Necker, Assistance publique hôpitaux de Paris, Paris, France.

A. Trinquand, N.R. dos Santos, and C. Tran Quang contributed equally to this article.

Abstract:

Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ε chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.

Revista: Cancer Discovery

Link: http://cancerdiscovery.aacrjournals.org/content/6/9/972.abstract