A pan-cancer single-cell landscape of tumor-infiltrating myeloid cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE154763 | GEO | 2021/02/04
REPOSITORIES: GEO
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Project description:Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which may promote or limit tumor outgrowth, but remain poorly understood. Here, we used single-cell RNA sequencing to map TIMs in non-small cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients’ blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets.
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Project description:Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer are among the cells most influenced by these molecules. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME. In tumors, TIM expansion and differentiation is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by cancer and immune cells. Nevertheless, the role of GM-CSF in tumors has not yet been fully elucidated. In this study, we show that GM-CSF activity is significantly affected by RNS-triggered post-translational modifications. The nitration of a single tryptophan residue in the sequence of GM-CSF nourishes the expansion of highly immunosuppressive myeloid subsets in tumor-bearing hosts. Importantly, tumors from colorectal cancer patients express higher levels of nitrated tryptophan compared to non-neoplastic tissues. Collectively, our data identify a novel and selective target that can be exploited to remodel the TME and foster protective immunity against cancer.
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Project description:Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. Although immune checkpoint inhibitors have improved outcomes in a subset of NSCLC patients, these effects are usually not durable. Thus, a more complete understanding of how immune niches within the tumor microenvironment (TME) promote NSCLC progression will allow us to build upon these advances. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-seq profiles of TIMs from several LUSC metastatic models with IMs of non-tumor bearing controls. We identified Spon1, a secreted extracellular matrix glycoprotein, as upregulated in TIMs and that Spon1 expression in LUSC tumors corresponds with poor survival. Bioinformatic analyses of the Cancer Genome Atlas (TCGA) revealed that LUSC tumors with high SPON1 expression significantly enriched for collagen extracellular matrix (ECM) signatures. Unexpectedly, we observed SPON1+ TIMs mediate their effects directly through LRP8 (ApoER2) on NSCLC cells, which results in TGFβ1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrate that SPON1+ TIMs are sufficient to promote NSCLC metastases. Additionally, we find that Spon1 loss in the host, or Lrp8 loss in cancer cells, results in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirm the relevance of the SPON1/LRP8/TGFβ1 axis with collagen production and survival in NSCLC patients. Taken together, our study describes how SPON1+ TIMs promotes collagen remodeling and NSCLC metastases through an LRP8-TGFβ1 signaling axis in lung cancer cells.
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Project description:Bladder cancer (BC) is one of the most common cancers in the world. T-cell immunoglobulin and mucin domain 1 (TIM-1) are involved in the progression of multiple tumors. However the role of TIM-1 in BC progression is poorly understood. In this study, we searched the Gene Expression Profiling Interactive Analysis (GEPIA) database and performed immunohistochemistry (IHC) to assess TIM-1 protein expression in bladder cancer (BC) patients. The results demonstrated that BC with high TIM-1 expression was associated with longer overall survival (OS) and disease-specific survival (DSS) than BC with low TIM-1 expression. Overexpression of TIM-1 inhibits BC cell proliferation in both cell culture and animal experiments. RNA sequencing data indicated that interferon-induced protein with tetratricopeptide repeats (IFIT) genes induced by interferon-α (IFN-α) were significantly enriched among the genes upregulated by TIM-1 overexpression. Mechanistically, our data revealed that TIM-1 promotes IFN-α release and activates the IFIT2/p-STAT1 pathway, which is known to be related to tumor cell proliferation. Moreover, knockdown of IFIT2 in TIM-1-overexpressing BC cells hinders the tumor suppressive effect of TIM-1. Our results revealed that TIM-1 is a potential molecular marker for BC prognosis and indicate that high TIM-1 expression suppresses BC cell proliferation in an IFIT2/p-STAT1-dependent manner.
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Project description:Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found two peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on the Tim-4 (T-cell immunoglobulin and mucin domain containing 4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FIP200 resulted in Tim-4+ TAM loss via ROS-mediated apoptosis, and elevated T cell-immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated CRIg (complement receptor of the Immunoglobulin superfamily) positive macrophages were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat ovarian cancer patients with peritoneal metastasis.
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