Professor Faculty of Medical Sciences-University Mohammed VI Polytechnic Ben Guerir, Morocco
Introduction/Rationale: Sézary syndrome (SS) is a rare and aggressive cutaneous T-cell lymphoma characterized by the clonal proliferation of malignant CD4⁺ T cells (Sézary cells, SCs) in the blood, skin, and lymph nodes. Despite existing therapies, many patients have poor prognosis and face relapse or resistance. SCs are known to co-express several immune markers and their ligands, prompting investigation into the ICOS/ICOSL axis, a pathway in T cell activation. Our finding aimed to characterize ICOS/ICOSL expression in SS and assess its potential as a therapeutic target.
Methods: ICOS and ICOSL expression were examined in SS patient samples, SS-derived cell lines, and other T-cell lymphoma subtypes. ICOSL isoform analysis was performed to identify variants and their structural features, using RT-PCR, Western blot, and Sanger sequencing. Functional assays assessed the effects of ICOS-ICOSL engagement or blockade on cell viability, signalling pathways and caspase-3 activation. An ICOS-Fc fusion protein, designed to bind all ICOSL isoforms, was tested for its ability to induce tumor clearance via antibody-dependent cell cytotoxicity (ADCC).
Results: Sézary cells aberratly co-express both ICOS and ICOSL in SCs. Notably, two ICOSL isoforms, ICOSL4.1 and ICOSL4.2 were identified having distinct cytoplasmic domains suggestive of distinct intracellular signaling potential. ICOSL engagement of ICOSL activated AKT signalling, ICOS/ICOSL blockade increased caspase-3 activation and enhanced tumor cell death. Therapeutic targeting of ICOSL with ICOS-Fc promoted immune-mediated tumor clearance through NK cell recruitment and ADCC.
Conclusion: We demonstrate that SCs co-express ICOS and ICOSL, enabling a cis/trans interaction that activates the AKT pathway and promotes tumor cell survival. Targeting this axis with ICOS-Fc induces immune-mediated tumor depletion. These findings position ICOSL as a novel, druggable therapeutic target in SS, offering promising new avenues for treatment in a disease with urgent unmet clinical need.
