KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target

Abstract

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).

Natural killer cell‐based signature: Prognostic analysis in head and neck squamous cell carcinoma

“…Previous studies have explored the role of these molecules in cancers. Cheminant et al found that KIR3DL2 is a underlying target of acute adult T‐cell leukemia 45 . Meanwhile, FCRL1 was also reported as a possible prognostic marker for diffuse large B‐cell lymphoma 46 .…”

“…Previous studies have explored the role of these molecules in cancers. Cheminant et al found that KIR3DL2 is a underlying target of acute adult T-cell leukemia 45.…”

Education and Empowering Special Forces to Eradicate Secret Defectors: Immune System-Based Treatment Approaches for Mature T- and NK-Cell Malignancies

“…To target lymphoma cells, the anti-KIR3DL2 mAb Lacutamab (IPH4102, IgG1), a humanized monoclonal anti-KIR3DL2 antibody was developed [77]. Preclinical data revealed promising results for Lacutamab, efficiently enabling autologous NK-cells to eliminate KIR3DL2 + primary ATLL cells in ex vivo assays [78]. In addition to ATLL, a Phase I trial for CTCL evaluated the safety and activity of Lacutamab in a cohort of 44 r/r CTCL patients (NCT02593046) [79].…”

KIR3DL2 may represent a novel therapeutic target in aggressive systemic peripheral T-cell lymphoma

“… 4 We have also recently shown that KIR3DL2 is the only KIR recurrently expressed in ATL, mostly in acute subtypes. 5 …”

“… 11 Moreover, we recently demonstrated that HTLV-1 infection triggered KIR3DL2 expression by normal CD4 + cells after 7 days of cell culture, suggesting that HTLV-1 influences KIR3DL2 expression either through infection-dependent chronic antigenic stimulation, viral integration, or the transcriptional activity of viral proteins. 5 Thus, in PTCL, it is conceivable that KIR3DL2, expressed either because of lineage properties or downstream of chronic antigenic stimulation, promotes PTCL cell survival through its inhibitory functions on the TCR pathway leading to reduced AICD.…”