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KIR3DL2 (CD158k) is a potential therapeutic target in primary cutaneous anaplastic large-cell lymphoma
M Battistella1,2,3, A Janin1,2,3, F Jean-Louis4
1Département de Pathologie, AP-HP, Hôpital Saint-Louis, Paris, 75010, France.
Background:
KIR3DL2, an inhibitory receptor expressed by natural killer cells and a subset of normal CD8(+) T cells, is aberrantly expressed in neoplastic cells in transformed mycosis fungoides and Sézary syndrome. Anti-KIR3DL2 targeted antibody therapy has shown potent activity in preclinical models for these diseases.
Objectives:
To examine the expression of KIR3DL2 and its potential use as a therapeutic target in patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL), the most aggressive cutaneous CD30(+) lymphoproliferative disease.
Methods:
Samples from 11 patients with pcALCL and three CD30(+) lymphoproliferative disease cell lines - Mac1, Mac2a and Mac2b - were used in KIR3DL2 expression studies using immunohistochemistry, flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. The effect of IPH4102, a monoclonal humanized IgG1 targeting KIR3DL2, was assessed by in vitro cytotoxicity assays against Mac1, Mac2a and Mac2b using allogeneic peripheral blood mononuclear cells as effectors.
Results:
KIR3DL2 mRNA and protein were found in all human samples of pcALCL, and in the Mac2a and Mac2b cell lines. KIR3DL2 protein expression was present on 85·8 ± 14·0% of CD30(+) skin-infiltrating tumour cells. In vitro functional studies showed that KIR3DL2(+) Mac2a and Mac2b pcALCL lines are sensitive to antibody-derived cytotoxicity mediated by IPH4102, through activation of natural killer cells, in a concentration-dependent manner.
Conclusions:
pcALCL tumour cells express KIR3DL2, and we provide preclinical proof of concept for the use of IPH4102, a humanized anti-KIR3DL2 antibody, to treat patients with primary cutaneous CD30(+) ALCL.
Insights
Primary cutaneous anaplastic large-cell lymphoma (pcALCL) cells express KIR3DL2. The anti-KIR3DL2 antibody IPH4102 demonstrates preclinical efficacy against pcALCL, supporting its potential as a targeted therapy.
Area of Science:
- Immunology
- Dermatology
- Oncology
Background:
- KIR3DL2 is an inhibitory receptor on natural killer cells and T cells.
- Aberrant KIR3DL2 expression is observed in transformed mycosis fungoides and Sézary syndrome.
- Targeted antibody therapy against KIR3DL2 shows promise in preclinical models.
Purpose of the Study:
- To investigate KIR3DL2 expression in primary cutaneous anaplastic large-cell lymphoma (pcALCL).
- To evaluate the therapeutic potential of targeting KIR3DL2 in pcALCL.
Main Methods:
- KIR3DL2 expression was analyzed in pcALCL patient samples and cell lines using immunohistochemistry, flow cytometry, and RT-qPCR.
- In vitro cytotoxicity assays assessed the efficacy of IPH4102, an anti-KIR3DL2 antibody, against pcALCL cell lines.
Main Results:
- KIR3DL2 mRNA and protein were detected in all pcALCL samples and specific cell lines (Mac2a, Mac2b).
- KIR3DL2 was expressed on a high percentage (85.8%) of CD30(+) tumor cells in pcALCL.
- IPH4102 induced concentration-dependent cytotoxicity against KIR3DL2(+) pcALCL cell lines via natural killer cell activation.
Conclusions:
- Tumor cells in pcALCL express KIR3DL2.
- Preclinical data support IPH4102 as a potential therapeutic antibody for pcALCL treatment.
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