Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance
Ashwin Ajith, … , Giorgio Trinchieri, Anatolij Horuzsko
Ashwin Ajith, … , Giorgio Trinchieri, Anatolij Horuzsko
Published August 31, 2023
Citation Information: J Clin Invest. 2023;133(21):e167951. https://doi.org/10.1172/JCI167951.
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Research Article Oncology

Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance

Abstract

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.

Authors

Ashwin Ajith, Kenza Mamouni, Daniel D. Horuzsko, Abu Musa, Amiran K. Dzutsev, Jennifer R. Fang, Ahmed Chadli, Xingguo Zhu, Iryna Lebedyeva, Giorgio Trinchieri, Anatolij Horuzsko

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Figure 2

scRNA-Seq analysis reveals alterations in immune landscape of TREM1-deficient TME in B16F10 melanoma.

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scRNA-Seq analysis reveals alterations in immune landscape of TREM1-defi...
scRNA-Seq analysis of tumor-infiltrating CD45+ cells from melanoma-bearing Trem1+/+ and Trem1–/– mice at day 22. For each experimental group, 4 biological replicates were pooled. (A) Data analyzed by Loupe browser and Seurat to generate t-SNE plot depicting differential cell clusters and their frequencies. Cluster identities based on expression of key gene signatures described in Methods. Bar graphs depict cluster proportions in each condition (Trem1+/+ and Trem1–/–). (B) t-SNE plots characterize expression of specific cluster markers for TICs in Trem1+/+ and Trem1–/– tumor-bearing mice. (C) Flow cytometry histogram plots depict PD-1 expression in tumor-infiltrating CD8+ and CD4+ T cells of Trem1+/+ or Trem1–/– mice and (D) in Trem1+/+ mice with indicated treatment (dot plots show a representative experiment performed in triplicate, n = 8–9 mice/group, mean ± SD). ***P < 0.001 assessed by 2-tailed Student’s t test for comparison between 2 groups (C and D).