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

Abstract

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 1α 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‐κβ 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.

Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

“…The anti-interleukin-10 (IL-10) antibody partially blocked this increase, suggesting that TAMs may trigger an increase in the population of FoxP3 + Treg cells in the tumor, thereby promoting the progression of HCC [25]. Mechanistically, Wu Q et al recently confirmed that TREM-1 + TAMs can respond to hypoxia and tumor metabolites via the ERK/NF-κβ pathway leading to accumulation of CCR6 + Foxp3 + Tregs [26]. This study highlights hypoxia-induced tumor immunosuppression by TREM-1 + TAMs that attracts CCR6 + Foxp3 + Tregs, and TREM-1 + TAMs confers HCC resistance to Programmed cell death 1 ligand 1 (PD-L1) treatment.…”

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…KCs can promote early tumor activity through different mechanisms: First, enhanced expression of PD-L1 202 and galectin-9 203 allows interactions with PD-1 and TIM3, respectively, resulting in repression of immunogenic T cell activation. Second, HCC signaling causes the upregulation of TREM1 on KCs, leading to the recruitment of CCR6 + Foxp3 + Tregs 204 and thus suppressing the cytotoxic T cell response. Finally, KCs recruit platelets through hyaluron-CD44 binding, an essential step in hepatocarcinogenesis.…”

Preparation of microspheres encapsulating sorafenib and catalase and their application in rabbit VX2 liver tumor

“…It has been reported that tumor hypoxia leads to the upregulation of PD-L1, which further inhibits the function of CD8 + T cells and induces immune escape [37]. Our results showed that SOR-CAT-PLGA MSs could down-regulate the expression of PD-L1, inhibit the apoptosis of CD8 + T cells, and increase the release of IFN-γ secreted by activated CD8 + T cells.…”