Constitutive PSGL-1 Correlates with CD30 and TCR Pathways and Represents a Potential Target for Immunotherapy in Anaplastic Large T-Cell Lymphoma

Simple Summary P-selectin glycoprotein ligand-1 (PSGL-1), coded by the SELPLG gene, is the major ligand of selectins and plays a pivotal role in tethering, rolling and extravasation of immune cells. PSGL-1 involvement in core molecular programs, such as SYK, PLC gamma 2, PI3K gamma or MAPK pathways, suggests additional functions beyond the modulation of cell trafficking. Recently, several studies identified a novel mechanism responsible for PSGL-1-mediated immune suppression in the tumor microenvironment and proved a novel concept of PSGL-1 as a critical checkpoint molecule for tumor immunotherapy. The immunotherapeutic approach has gained an ever-growing interest in the treatment of several hematological malignancies, and in particular, novel targets for immunotherapy are still highly sought-after in T-cell lymphomas. Based on our results obtained through gene expression profiling and immunohistochemical analysis, PSGL-1, already suggested as a potential target in multiple myeloma humoral immunotherapy, could be considered noteworthy among the candidates. Due to the high expression of P-selectin glycoprotein ligand-1 (PSGL-1) in lymphoproliferative disorders and in multiple myeloma, it has been considered as a potential target for humoral immunotherapy, as well as an immune checkpoint inhibitor in T-cells. By investigating the expression of SELPLG in 678 T- and B-cell samples by gene expression profiling (GEP), further supported by tissue microarray and immunohistochemical analysis, we identified anaplastic large T-cell lymphoma (ALCL) as constitutively expressing SELPLG at high levels. Moreover, GEP analysis in CD30+ ALCLs highlighted a positive correlation of SELPLG with TNFRSF8 (CD30-coding gene) and T-cell receptor (TCR)-signaling genes (LCK, LAT, SYK and JUN), suggesting that the common dysregulation of TCR expression in ALCLs may be bypassed by the involvement of PSGL-1 in T-cell activation and survival. Finally, we evaluated the effects elicited by in vitro treatment with two anti-PSGL-1 antibodies (KPL-1 and TB5) on the activation of the complement system and induction of apoptosis in human ALCL cell lines. In conclusion, our data demonstrated that PSGL-1 is specifically enriched in ALCLs, altering cell motility and viability due to its involvement in CD30 and TCR signaling, and it might be considered as a promising candidate for novel immunotherapeutic approaches in ALCLs.

Automated summary

PSGL-1, as the major ligand of selectins, plays a crucial role in immune cell tethering, rolling, and extravasation. Recent studies have identified a novel mechanism of PSGL-1-mediated immune suppression in the tumor microenvironment, positioning it as a critical checkpoint molecule in tumor immunotherapy. The high expression of PSGL-1 in lymphoproliferative disorders, particularly in T-cell lymphomas, suggests its potential as a target for immunotherapy. Through gene expression profiling and immunohistochemical analysis, PSGL-1 was found to be enriched in ALCLs, altering cell motility and viability, and presenting itself as a promising candidate for novel immunotherapeutic approaches.