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

• Published in: The Journal of clinical investigation 2023-11, Vol.133 (21), p.1-18
• Main Authors: Ajith, Ashwin, Mamouni, Kenza, Horuzsko, Daniel D, Musa, Abu, Dzutsev, Amiran K, Fang, Jennifer R, Chadli, Ahmed, Zhu, Xingguo, Lebedyeva, Iryna, Trinchieri, Giorgio, Horuzsko, Anatolij
• Format: Article
• Language: English
• Subjects: Analysis; Animals; B cells; Biomedical research; Cancer; Cell culture; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell receptors; Cell survival; Cytotoxicity; Development and progression; Disease Models, Animal; Down-regulation; Drug resistance; Drug therapy; Fibrosarcoma; Flow cytometry; Health aspects; Humans; Immune checkpoint; Immunity; Inflammatory diseases; Liver cancer; Lymphocytes; Lymphocytes T; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Mice; Myeloid Cells - pathology; Myeloid-Derived Suppressor Cells; Oncology; Patients; PD-1 protein; Peptides; Physiological aspects; Prevention; RNA sequencing; Sarcoma; Solid tumors; Suppressor cells; T cells; T-Lymphocytes, Cytotoxic - pathology; Therapeutics; Triggering Receptor Expressed on Myeloid Cells-1 - genetics; Triggering Receptor Expressed on Myeloid Cells-1 - metabolism; Tumor Microenvironment; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI167951

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.