TLR2 signaling regulates T cell exclusion in pancreatic ductal adenocarcinoma
Jacqueline Plesset, Meredith L. Stone, John C. McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S. Thickens, Devora Delman, Gregory L. Beatty
Jacqueline Plesset, Meredith L. Stone, John C. McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S. Thickens, Devora Delman, Gregory L. Beatty
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Research Article Immunology Inflammation Oncology

TLR2 signaling regulates T cell exclusion in pancreatic ductal adenocarcinoma

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 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 KO 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.

Authors

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

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Figure 2

Innate immune signaling molecules correlate with increased tumor immune infiltration in PDAC.

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Innate immune signaling molecules correlate with increased tumor immune ...
(A) PCA plot of T cellhi versus T celllo bulk tumor RNA-seq. (B) Innate signaling pathway heatmap of T cellhi versus T celllo bulk tumor RNA-seq. (C) Normalized TLR2 DESeq expression from bulk RNA-seq data (Mann-Whitney U test performed). (D) Study design of T cellhi versus T celllo end point study. T cellhi (2838c3) or T celllo (PDA.69) cells (1 × 106) were implanted s.c. into Tlr2+/+ mice (n = 8/group) on Day 0. Tumors were extracted with necropsy on day 20. (E) CD8+TLR2+ T cell (CD45+CD3+CD8+TLR2+) per gram. Data shown is n = 3 experimental replicates (Mann-Whitney U test performed). (F) TLR2+ macrophages (CD45+CD11b+F480+CD3–CD19–Ly6G– TLR2+) per gram. Data shown is n = 2 experimental replicates (Mann-Whitney U test performed). (G) TLR2+ DCs (CD45+CD11c+F480–CD3–CD19–Ly6G– TLR2+) per gram. Data shown is n = 3 experimental replicates (Mann-Whitney U test performed). (H) Heatmap of TCGA data of n = 172 patients with pancreas cancer. (I) Gene correlation plot of TCGA data. (J and K) Normalized TLR2 RNA Expression of high (quartiles 3 and 4) versus low (quartiles 1 and 2) CD3E and CD8A gene expression from TCGA data. (L) Labeled UMAP of single cell RNA-seq data taken from 6 PDAC patients. (M) UMAP of TLR2 expression in single cell RNA-seq data divided into T cellhi versus T celllo patients. T cellhi patients: ≥30% of cells found in their tumors are T cells. T celllo patients: ≤10.5% of cells in their tumors are T cells (22). (N) Dot plot of TLR2, CD3E, CD8A, and CD4 genes from single cell RNA-seq dataset.