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 4

TLR2 is a therapeutic target in PDAC.

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TLR2 is a therapeutic target in PDAC. (A) Study schematic for B–F. T cel...
(A) Study schematic for B–F. T celllo (PDA.69) cells (1 × 106) were implanted s.c. into Tlr2+/+ or Tlr2–/– mice (n = 10/group) on day 0. Data are representative of 1 experiment. (B) Mean tumor growth (2-way ANOVA test performed). (C) Tumor size day 35 (Mann-Whitney U test performed). (D) Overall survival (Mantel-Cox test performed). (E) Representative images of tumors stained for CD3 (pink), Ki67 (yellow), and CK19 (blue). Scale bar: 50 μm. (F) Analysis of T cell (CD3 stained) per tumor area (CK19 stained) from E (Mann-Whitney U test performed). (G) Study schematic for H and I. T celllo (PDA.69) cells (1 × 105) were orthotopically implanted into Tlr2+/+ (n = 8) or Tlr2–/– (n = 7) mice. Ten days later, tumors were surgically resected. Mice were monitored for overall survival. (H) SAA serum level measured by ELISA (Wilcoxon matched pairs signed rank test performed, or Mann-Whitney U test performed for unpaired groups). Data shown are from n = 2 experimental replicates. (I) Overall survival (Mantel-Cox test performed). Data are representative of n = 3 experimental replicates. (J) Study schematic for K–M. Tlr2+/+ mice were treated with aTLR2 (0.2 mg/dose, Sino) on day –2. On day 0, mice were s.c. challenged with T celllo (PDA.69) cells (1 × 106). (K) Mean tumor growth curves (2-way ANOVA test performed). (L) Tumor volume day 26 (Mann-Whitney U test performed). (M) Overall survival (Mantel-Cox test performed). (N) Study schematic for O. On day 0, Tlr2+/+ mice were orthotopically implanted with 5 × 105 T celllo (6694c2) cells. aTLR2 (0.2 mg/dose) was administered i.p. every 3–4 days starting on day –1 (prophylactic, red arrows) or day 10 (therapeutic, blue arrows). (O) Tumor weight on day 15 after tumor implantation (1-way ANOVA with Tukey correction).