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 1

ODN1585 improves the efficacy of anti–PD-1 therapy for colorectal peritoneal metastases.

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ODN1585 improves the efficacy of anti–PD-1 therapy for colorectal perito...
(A) Schematic timeline of experimental setting and analysis for peritoneal tumor models. Mice received control and isotype antibodies (Con+Iso), ODN1585 (5 nmol/mouse) and Iso (ODN+Iso), control and anti–PD-1 (10 mg/kg, Con+αPD1), or ODN1585 and anti–PD-1 (ODN+αPD1) every 3days. (B–D) Mice were inoculated with MC38-luciferase-GFP (1 million cells/mouse, i.p.). (B) Bioluminescence images from individual WT mice at the indicated times after the peritoneal tumor challenge. One representative of 2 independent experiments is depicted. (C) Bioluminescence was measured as photons per second at the indicated times after the peritoneal tumor challenge. (D) Kaplan-Meier survival curve for 49 days. (E and F) BALB/cByJ mice were administered with CT26-luciferase-GFP cells i.p. (1 million cells/mouse). (E) Bioluminescence was measured as photons per second at the indicated times after peritoneal tumor challenge. (F) Kaplan-Meier survival curve. (C and E) Data are from 2 separate experiments. Symbols represent individual mice. Statistical differences were determined using a 2-way ANOVA with Tukey’s multiple comparisons test. (D and F) Data are from 2 separate experiments. Statistical differences were determined using log-rank test adjusted by Bonferroni’s testing. *P < 0.05, **P < 0.01. Only the significant differences are labeled.