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

Beatrice Belmonte,Pier Piccaluga,Paolo Amico,Alessandro Gulino,Alessandro Mangogna,Antonino Maiorana,Valeria Cancila,Andrea Balduit,Davide Vacca,Sara Capolla,Mohsen Navari,Tiziana Salviato,Walter Arancio,Giorgio Bertolazzi,Federica Ferrante,Gaia Morello,Ines Ferrara,Paolo Macor,Carmela Balistreri

doi:10.3390/cancers13122958

Abstract

Simple SummaryP-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, PLCγ2, PI3Kγ 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.

Highlights

P-selectin glycoprotein ligand-1 (PSGL-1) represents the major ligand for selectins (Platelets, Leukocytes and Endothelium selectins, or P, L- and E-selectins), playing a relevant role in regulating the tethering, rolling and extravasation of cellular components of the immune system from peripheral blood to inflamed tissues [1,2,3]
We evaluated the expression of SELPLG in 678 samples, comprising malignant and non-malignant T- and B-cells, by gene expression profiling (GEP) analysis
No statistically significant difference was determined in SELPLG gene expression between anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphomas (ALCLs) specimens (Figure S1C)

Summary

Introduction

P-selectin glycoprotein ligand-1 (PSGL-1) represents the major ligand for selectins (Platelets, Leukocytes and Endothelium selectins, or P-, L- and E-selectins), playing a relevant role in regulating the tethering, rolling and extravasation of cellular components of the immune system from peripheral blood to inflamed tissues [1,2,3]. PSGL-1 has been shown to induce caspase-independent apoptosis in activated T-cells [10], suppress the late-phase immune response in lymph nodes via regulatory T-cells [11] and stimulate a tolerogenic function of dendritic cells, resulting in the regulation of the immune response [12]. It has emerged as an immune checkpoint regulator promoting T-cell exhaustion [13] reasonably through the up-regulation of programmed cell death protein-1 (PD-1) [14] and IL-2 down-regulation [15]. Due to its previously unknown selectin-independent roles and its ability to induce T-cell exhaustion, PSGL-1 has been proposed as a potential target for immune modulation [22] and humoral immunotherapy [23] because it is highly expressed in lymphoproliferative disorders with plasmocytic differentiation and in multiple myelomas (MMs) as well [23,24,25]

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