Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers

Authors

• Andreas Stephanou, Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
• Madhav Mantri, Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
• Divya Shankaranarayanan, Division of Nephrology and Hypertension, George Washington University, Washington DC, USA.
• Carol Li, Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA.
• Mila Lagman, Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA.
• Jenny Xiang, Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY, USA.
• Chendong Pan, Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY, USA.
• Yanjie Sun, Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY, USA.
• Thangamani Muthukumar, Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA.
• Khaled Machaca, Calcium Signaling Group, Research Department, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar; Department of Systems and Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
• Iwijn De Vlaminck, Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA. Electronic address: vlaminck@cornell.edu.
• Manikkam Suthanthiran, Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA. Electronic address: msuthan@med.cornell.edu.

Document Type

Journal Article

Publication Date

2-13-2026

Journal

Human immunology

Volume

87

Issue

4

DOI

10.1016/j.humimm.2026.111687

Abstract

Store-operated calcium entry (SOCE) plays a critical role in regulating intracellular calcium signaling and is essential for immune cell functions. SOCE blockade with the pyrazole derivative BTP2 has been explored as an anti-inflammatory strategy in preclinical models, and Zegocractin (CM4620) is under clinical investigation as a CRAC channel inhibitor with activity in multiple tissues, including immune cells. However, the cell type-specific consequences of SOCE blockade under defined activation contexts remain incompletely understood. Here, we used multiplexed single-cell RNA sequencing to investigate the effects of two prototypic SOCE blockers, BTP2 and CM4620, on polyclonally stimulated, normal human peripheral blood mononuclear cells (PBMCs) in a phytohemagglutinin (PHA)-driven T-cell activation model. The data revealed that SOCE blockade suppressed cytotoxicity-associated transcriptional programs in CD8 effector T cells and natural killer (NK) cells, restoring them to levels comparable to unstimulated cells. At the same time, SOCE blockade allowed CD4 regulatory T cells to retain transcriptional signatures associated with immune regulation. These results indicate that, in this experimental model, SOCE blockade dampens cytotoxic programs while maintaining tolerance signatures, suggesting a potential avenue for targeted immune modulation in transplantation and other immune-mediated conditions. SIGNIFICANCE STATEMENT: Store-operated calcium entry (SOCE) is essential for immune activation, but broad immunosuppression can cause significant side effects. Using single-cell transcriptomics in a phytohemagglutinin (PHA)-driven T-cell activation model, we show that SOCE blockade with BTP2 or CM4620 suppresses pro-inflammatory and cytotoxic programs in CD8 effector T cells and NK cells while preserving tolerance-associated pathways in CD4 regulatory T cells. These findings suggest that SOCE blockade may provide a more targeted form of immune modulation, warranting future head-to-head comparisons with conventional immunosuppressants. Our results highlight the potential of SOCE blockers to reduce immune-mediated damage while maintaining tolerance, motivating further functional and translational studies in transplantation and other immune-mediated conditions.

APA Citation

Stephanou, Andreas; Mantri, Madhav; Shankaranarayanan, Divya; Li, Carol; Lagman, Mila; Xiang, Jenny; Pan, Chendong; Sun, Yanjie; Muthukumar, Thangamani; Machaca, Khaled; De Vlaminck, Iwijn; and Suthanthiran, Manikkam, "Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers" (2026). GW Authored Works. Paper 8715.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8715

Department

Medicine