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Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

ABSTRACT: Summary Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer. Graphical abstract Highlights • Several myeloid cell subsets express surface LAP• Myeloid cells that express surface LAP possess immunosuppressive properties• LAP expressing myeloid cells induce Tregs and inhibit effector T cell function• LAP expressing myeloid cells promote tumor growth Immunology; Cancer

SUBMITTER: Gabriely G

PROVIDER: S-EPMC8602030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

Project description:Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-b on their surface, LAPHi MCs, that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-b inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promote Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

2021-11-24 | GSE174077 | GEO

Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

Project description:Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells

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Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells.

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Targeting latency-associated peptide promotes antitumor immunity.

Project description:Regulatory T cells (Tregs) promote cancer by suppressing antitumor immune responses. We found that anti-LAP antibody, which targets the latency-associated peptide (LAP)/transforming growth factor-β (TGF-β) complex on Tregs and other cells, enhances antitumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma, and glioblastoma. Anti-LAP decreases LAP+ Tregs, tolerogenic dendritic cells, and TGF-β secretion and is associated with CD8+ T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8+ T cells and reduces CD103+ CD8 T cells in draining lymph nodes and the spleen. We identified a role for CD103+ CD8 T cells in cancer. Tumor-associated CD103+ CD8 T cells have a tolerogenic phenotype with increased expression of CTLA-4 and interleukin-10 and decreased expression of interferon-γ, tumor necrosis factor-α, and granzymes. Adoptive transfer of CD103+ CD8 T cells promotes tumor growth, whereas CD103 blockade limits tumorigenesis. Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy.

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CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.

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The Role of Tumor-Associated Myeloid Cells in Modulating Cancer Therapy.

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