LAUSR

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 TAX mRNA expression levels were assessed by PrimeFlowTM RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo autologous 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 KIR3DL2 might 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).