Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer

Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1 alpha induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1(+)) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8(+) T cells and induced CD8(+) T-cells apoptosis. Biological and functional assays showed that TREM-1(+) TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1(+) TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1(+) TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1(+) TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1(+) TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-kappa beta pathway in response to hypoxia and tumor metabolites leading to CCR6(+)Foxp3(+) Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6(+)Foxp3(+) Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6(+)Foxp3(+) Treg recruitment was crucial for TREM-1(+) TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1(+) TAMs attracting CCR6(+)Foxp3(+) Tregs, and TREM-1(+) TAMs endowed HCC with anti-PD-L1 therapy resistance.