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ResearchIn-Press PreviewImmunologyInflammationOncology Open Access | 10.1172/jci.insight.195329

TLR2 signaling regulates T cell exclusion in pancreatic ductal adenocarcinoma

Jacqueline Plesset,1 Meredith L. Stone,1 John C. McVey,1 Heather Coho,1 Kelly Markowitz,1 Kayjana Coho,1 Jesse Lee,1 Anna S. Thickens,1 Devora Delman,1 and Gregory L. Beatty1

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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1Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States of America

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Published April 3, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.195329.
Copyright © 2026, Plesset et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 3, 2026 - Version history
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying Toll-like receptor 2 (TLR2) as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic knockout models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.

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  • Version 1 (April 3, 2026): In-Press Preview
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