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

×

Figure 1

TREM1 deficiency and anti-TREM1 treatment diminish B16F10 tumor growth by altering tumor immune infiltrates.

Options: View larger image (or click on image) Download as PowerPoint
TREM1 deficiency and anti-TREM1 treatment diminish B16F10 tumor growth b...
(A) Tumor growth curves for B16F10 melanoma in Trem1+/+ and Trem1–/– mice (mean ± SEM, n = 9 mice/group). Representative microscopic images of tumors from indicated groups on day 22. (B) Schematic illustration describes treatment protocol with TREM1 inhibitor VJDT on B16F10 melanoma in Trem1+/+ mice. Treatment initiated on eighth day of tumor growth followed every alternate day with VJDT (20 mg/kg) or vehicle (DMSO) until day 20. Tumor growth curves calculated by individual measurements recorded every alternate day (n = 9 mice/group, mean ± SEM). Representative microscopic images of tumors from indicated groups on day 22. (C–J) Tumors harvested on day 22. Flow cytometry analysis and frequency of cells in gated immune subsets are depicted (dot plots show a representative experiment performed in triplicate, n = 7–9 mice/group, mean ± SD shown). (C) Frequency of CD11b+F4/80+Gr-1– TAMs and CD11b+F4/80–Gr-1+ MDSC infiltrates in Trem1+/+ or Trem1–/– mice and (D) in Trem1+/+ mice with indicated treatment. (E) Frequency of CD11b+Gr-1+Ly6ChiLy6G– M-MDSC and CD11b+Gr1+Ly6CloLy6G+ PMN-MDSCs in Trem1+/+ or Trem1–/– mice and (F) in Trem1+/+ mice with indicated treatment. (G) Frequency of exhausted CD8+Tim-3+CTLA-4+ T cells in Trem1+/+ or Trem1–/– mice and (H) in Trem1+/+ mice with indicated treatment. (I) Frequency of cytotoxic CD8+GzmB+CD25+ T cells in Trem1+/+ or Trem1–/– mice and (J) in Trem1+/+ with indicated treatment. **P < 0.01; ***P < 0.001; ****P < 0.0001 assessed by 2-way ANOVA for multiple comparison of longitudinal tumor growth between groups (A and B [tumor growth]) or 2-tailed Student’s t test for comparison between 2 groups (C–H).