Tumor-associated platelets suppress T-Cell function and promote immune evasion in TNBC via the P-selectin/ P-selectin glycoprotein ligand-1 Pathway.

Smith-Oliver, M. R., Gautam, D., Petrarca, G. C., Sullivan, M. E., Clarke, E. M., Goggi, G., Spasic, M., Kane, N., Brown, J., Roweth, H. G. ORCID: https://orcid.org/0000-0002-1100-8409, Baginska, J., Garrido-Castro, A. C., Davenport, P., McAllister, S. S. and Battinelli, E. M. (2026) Tumor-associated platelets suppress T-Cell function and promote immune evasion in TNBC via the P-selectin/ P-selectin glycoprotein ligand-1 Pathway. Cancer research communications. ISSN 2767-9764 doi: 10.1158/2767-9764.CRC-26-0187 (In Press)

Abstract/Summary

Tumor-associated platelets (TAPs), which are reprogrammed by tumor-derived signals to acquire immunosuppressive properties, represent an emerging mechanism of immune evasion in triple-negative breast cancer (TNBC). Although immune checkpoint inhibitors (ICIs) have shown promise, their efficacy is frequently limited by T cell exhaustion and therapeutic resistance. Here, we demonstrate that TAPs, unlike healthy circulating platelets, induce T cell dysfunction through platelet-derived P-selectin, which engages P-selectin glycoprotein ligand-1 (PSGL-1) on T cells. This interaction promotes immunosuppressive signaling, driving T cell exhaustion and impairing anti-tumor cytotoxicity. Using in vitro co-culture systems and in vivo TNBC models, we show that disruption of the P-selectin-PSGL-1 axis, including pharmacologic blockade with the FDA-approved anti-P-selectin antibody Crizanlizumab, restores T cell function and enhances responsiveness to immune checkpoint blockade. Notably, PSGL-1, traditionally recognized for its role in leukocyte trafficking and immune regulation, is co-opted by TAPs to suppress T cell activity, revealing a mechanism of platelet-mediated immune modulation. These findings establish TAPs as active regulators of anti-tumor immunity and identify the P-selectin-PSGL-1 axis as a therapeutically actionable target to overcome resistance to immunotherapy in TNBC.

Item Type	Article
URI	https://centaur.reading.ac.uk/id/eprint/130672
Identification Number/DOI	10.1158/2767-9764.CRC-26-0187
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	American Association for Cancer Research
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