| Autor: |
Cheminant, Morgane, Lhermitte, Ludovic, Bruneau, Julie, Sicard, Hélène, Bonnafous, Cécile, Touzart, Aurore, Bourbon, Estelle, Ortonne, Nicolas, Genestier, Laurent, Gaulard, Philippe, Palmic, Patricia, Suarez, Felipe, Frenzel, Laurent, Naveau, Louise, Dussiot, Mickaël, Waast, Laetitia, Avettand-Fenoel, Véronique, Brouzes, Chantal, Pique, Claudine, Lepelletier, Yves, Asnafi, Vahid, Marçais, Ambroise, Hermine, Olivier |
| Zdroj: |
Blood; 20220101, Issue: Preprints |
| Abstrakt: |
Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by HTLV-1, that encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into four subtypes (ie, smoldering, chronic, acute, lymphoma). We determined whether natural killer receptors (NKR) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 ATL patients. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs. lymphoma- and chronic/smoldering-type ATL (36/40, 4/16 and 1/15, respectively; p=0.001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. KIR3DL2 expression was correlated with promoter demethylation by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAXmRNA expression levels were assessed by PrimeFlowTMRNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAXmRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2expression. Ex vivoautologous antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2-positive primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2might be triggered by HTLV-1 infection and is correlated with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (NCT04984837). |
| Databáze: |
Supplemental Index |
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