Discovery of a new immunotherapeutic target against B-lymphocyte lymphoma

Authors and affiliations:
João L. Pereira^1,2,3, Liliana Arede¹, Francisca Ferreira^1,2,4, Andreia Matos^1,5,6,7,8, Dulcineia Pereira^1,2,9, Rita F. Santos^1,10,11, Alexandre M. Carmo^1,10, Maria J. Oliveira^1,3,5, José C. Machado^1,2,3, Delfim Duarte^1,3,9, Nuno R. dos Santos^1,2

¹ i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

² IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.

³ Faculty of Medicine, University of Porto, Porto, Portugal.

⁴ Master´s Program in Bioengineering; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, and Faculty of Engineering, University of Porto, Porto, Portugal.

⁵ INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.

⁶ ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.

⁷ Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisboa, Portugal.

⁸ Ecogenetics and Human Health, Environmental Health Institute, Faculty of Medicine, University of Lisbon, Lisboa, Portugal

⁹ Department of Hematology and Bone Marrow Transplantation, IPO Porto, Porto, Portugal

¹⁰ IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.

¹¹ ESS – IPP, School of Health, Polytechnic of Porto, Porto, Portugal

Abstract:
Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic coculture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4+ and CD8+ T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-Myc lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.

Journal: Leukemia

Link: https://www.nature.com/articles/s41375-024-02446-w