STAT1 Phosphorylation at Y701 Drives Interferon Response in Sarcoma Cells

Undifferentiated pleomorphic sarcoma (UPS) is a genetically complex soft tissue sarcoma with few therapeutic options once disease becomes advanced. Immune checkpoint blockade may benefit a subset of patients, particularly those whose tumours show elevated expression of Programmed Cell Death Ligand 1 (PD-L1) and an inflamed tumour microenvironment. In earlier transcriptomic analyses, the researchers found that Signal Transducer and Activator of Transcription 1 (STAT1), a key mediator of interferon-γ (IFN-γ) signalling, was enriched in a cohort of UPS cases with elevated PD-L1 levels that had shown improved clinical outcomes.

To probe STAT1’s role in UPS biology, the team worked with primary human UPS cell lines, examining what happens when STAT1 is lost and when either wild-type STAT1 or a phosphorylation-deficient variant is overexpressed. The variant carries a tyrosine-to-phenylalanine substitution at position 701 (Y701F), which prevents phosphorylation at that residue.

Treatment with IFN-γ reduced cell counts, increased cell death, and induced secretion of CXCR3 ligands, and all three effects depended on the presence of STAT1. This places STAT1 centrally in the pathway through which IFN-γ exerts antitumour effects in these cells.

The phosphorylation site proved critical. Overexpression of wild-type STAT1 restored IFN-γ-mediated cell death and cytokine secretion, but the Y701F phospho-mutant did not. The result highlights the importance of Y701 phosphorylation for STAT1-associated antitumour functions in UPS cells.

Gene expression changes linked to STAT1 Y701 phosphorylation status varied between cell lines, indicating that the downstream transcriptional response is cell line specific rather than uniform across UPS samples.

Together, the findings clarify how STAT1, and specifically its Y701 phosphorylation, mediates IFN-γ signalling and the associated phenotypes in primary UPS cells. The study, conducted in cell lines rather than patients, underscores the need for further exploration of STAT1 phosphorylation in tumour-immune interactions within UPS, a step that could inform which patients might benefit from immunotherapy approaches already showing promise in the PD-L1-high, inflamed subset of this disease.

Subject of Research: Role of STAT1 expression and Y701 phosphorylation in interferon-γ signalling and antitumour phenotypes in primary undifferentiated pleomorphic sarcoma cells

Article Title: The effect of STAT1 expression and the Y701 phosphorylation on primary Undifferentiated Pleomorphic Sarcoma cells

Article References: Coward, V. S., Gokgoz, N., Tsoi, K. M., Wunder, J. S., & Andrulis, I. L. (2026). The effect of STAT1 expression and the Y701 phosphorylation on primary Undifferentiated Pleomorphic Sarcoma cells. PLOS One, 21(10), e0361295. https://doi.org/10.1371/journal.pone.0361295

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361295

Keywords: undifferentiated pleomorphic sarcoma, STAT1, Y701 phosphorylation, interferon-gamma, PD-L1, CXCR3 ligands, soft tissue sarcoma, immune checkpoint blockade, tumour microenvironment, cell lines, effect, expression