Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases
Ting Jiang, Hongji Zhang, Yiming Li, Preethi Jayakumar, Hong Liao, Hai Huang, Timothy R. Billiar, Meihong Deng
Ting Jiang, Hongji Zhang, Yiming Li, Preethi Jayakumar, Hong Liao, Hai Huang, Timothy R. Billiar, Meihong Deng
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Research Article Immunology Oncology

Intraperitoneal injection of class A TLR9 agonist enhances anti–PD-1 immunotherapy in colorectal peritoneal metastases

Abstract

Peritoneal metastases are associated with a low response rate to immune checkpoint blockade (ICB) therapy. The numbers of peritoneal resident macrophages (PRMs) are reversely correlated with the response rate to ICB therapy. We have previously shown that TLR9 in fibroblastic reticular cells (FRCs) plays a critical role in regulating peritoneal immune cell recruitment. However, the role of TLR9 in FRCs in regulating PRMs is unclear. Here, we demonstrated that the class A TLR9 agonist, ODN1585, markedly enhanced the efficacy of anti–PD-1 therapy in mouse models of colorectal peritoneal metastases. ODN1585 injected i.p. reduced the numbers of Tim4+ PRMs and enhanced CD8+ T cell antitumor immunity. Mechanistically, treatment of ODN1585 suppressed the expression of genes required for retinoid metabolism in FRCs, and this was associated with reduced expression of the PRM lineage–defining transcription factor GATA6. Selective deletion of TLR9 in FRCs diminished the benefit of ODN1585 in anti–PD-1 therapy in reducing peritoneal metastases. The crosstalk between PRMs and FRCs may be utilized to develop new strategies to improve the efficacy of ICB therapy for peritoneal metastases.

Authors

Ting Jiang, Hongji Zhang, Yiming Li, Preethi Jayakumar, Hong Liao, Hai Huang, Timothy R. Billiar, Meihong Deng

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Figure 5

Activation of TLR9 negatively regulates retinoid metabolism in FRCs.

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Activation of TLR9 negatively regulates retinoid metabolism in FRCs. (A–...
(A–D) Abundance of Wt1, Aldh1a1, and Aldh1a2 transcripts in mouse FRCs (A) with control, ODN1585 (2.5 nM),or LPS (1 μg/mL) treatment for 18 hours; (B) with ODN1585 (2.5 nM), ODN1826 (2.5 nM), or ODN2395 (2.5 nM) treatment for 18 hours; (C) with ODN1585 (2.5 nM) treatment for indicated time periods; or (D) with indicated concentrations of ODN1585 treatment for 18 hours. (E) Percentage of ALDEFLUOR+ FRC in vivo. WT and Tlr9–/– mice were treated with PBS or ODN1585 (5 nmol/mouse, i.p.) for 18 hours. ALDEFLUOR+ FRCs in the omentum and mesenteric adipose tissue were analyzed using flow cytometry. (F) Percentage of ALDEFLUOR+ FRCs in vitro. WT and Tlr9–/– FRCs were treated with PBS or ODN1585 (2.5 nM) for 18 hours. ALDEFLUOR+ FRCs were analyzed using flow cytometry. (G) Abundance of WT1, ALDH1A1, and ALDH1A2 transcripts in human FRCs with control, ODN2261 (2.5 nM), or LPS (1 μg/mL) treatment for 18 hours. (A–D, F, and G) The experiments were repeated 3 times. Data are shown as mean ± SD from 1 representative experiment. (E) Data are shown as mean ± SD from 2 separate experiments. Symbols represent individual mice. Statistical differences were determined using 2-way ANOVA with Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01. Only the significant differences are labeled.