Proteomics of immune cells from liver tumors reveals immunotherapy targets
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228571 | GEO | 2023/04/18
REPOSITORIES: GEO
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Project description:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, as well as monocyte/macrophages, and CD4+ and CD8+ T cells isolated from tumors, livers, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2 is upregulated in chronically activated CD8+ T cells in tumors but is not present during the canonical T cell activation program. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).
2023-04-18 | GSE229400 | GEO
Project description:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).
2023-04-19 | PXD040957 | Pride
Project description:Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumors. Although this function is traditionally attributed to dendritic cells, tumor-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumor-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbor hyperactive cysteine protease activity in their lysosomes which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) targeted to lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases present specifically inside lysosomes of TAMs, improves their ability to cross-present antigens, and attenuates tumor growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumor regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.
2021-10-14 | PXD028037 | Pride
Project description:We investigated the sub-proteomes of different functional compartments in astrocyte and neurons in the striatum. We compared the proteomes to the cell-specific RNA profiles of neurons and astrocytes from these analyses. We found one gene and protein that was highly expressed in neurons and astrocytes called SAPAP3. Knockout of this gene product results in an OCD-like phenotype in mouse. RNA-seq of astrocytes and bulk RNA-seq analyses of this mouse model revealed very low DEGs.
2023-01-13 | GSE184773 | GEO
Project description:<p>Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10<sup>-5</sup>) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10<sup>-6</sup>) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.</p>
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Project description:Hyaluronan receptor LYVE-1 is expressed by liver sinusoidal endothelial cells (LSEC), lymphatic endothelial cells and specialized macrophages. Besides binding hyaluronan, LYVE-1 mediates adhesion of leukocytes and cancer cells to endothelial cells. Here, we analyzed the impact of LYVE-1 on physiological liver functions and metastasis. Mice with deficiency of Lyve-1 (Lyve-1 KO) were analyzed using histology, immunofluorescence, RNA sequencing, plasma proteomics and flow cytometry. Liver metastasis was studied by intrasplenic/intravenous injection of melanoma (B16F10luc2, WT31) or colorectal carcinoma (MC38) cell lines. Results: Hepatic architecture, liver size, endothelial differentiation and angiocrine functions were unaltered in Lyve-1 KO mice. Hyaluronan plasma levels were significantly increased in Lyve-1-KO mice; besides, plasma proteomics revealed increased carbonic anhydrase-2 and decreased FXIIIA, potential modulators of metastatis. Furthermore, gene expression analysis of LSEC indicated regulation of immunological pathways. Therefore, liver metastasis of a highly and of a weekly immunogenic tumor, i.e. melanoma and colorectal carcinoma (CRC), was analyzed in Lyve-1 KO mice. Hepatic metastasis of B16F10 luc2 and WT31 melanoma cells, but not MC38 CRC cells, was significantly reduced in Lyve-1 KO mice. While short-term adhesion assays with B16F10 luc2 cells in vivo did not show differences between Lyve-1 KO and wild-type mice, increased numbers of resident hepatic CD4+, CD8+ and regulatory T cells were detected in Lyve-1 KO livers. In addition, iron deposition was detected in F4/80+ liver macrophages known to exert pro-inflammatory effects. Conclusions: LYVE-1 deficiency controlled hepatic metastasis in a tumor cell-specific manner reducing hepatic metastasis of melanoma, but not CRC. Anti-tumorigenic effects are likely due to enhancement of the resident hepatic immune microenvironment.
2023-03-11 | PXD032717 | Pride
Project description:Metastasis is the primary cause of cancer mortality. Cancer frequently metastasizes to the liver. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Mechanistically, liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in both preclinical models and patients. Liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T-cell survival, and reduces hepatic siphoning. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T-cell deletion and the combination of liver-directed radiotherapy and immunotherapy is a novel therapeutic strategy to promote systemic anti-tumour immunity.
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2024-03-21 | GSE262135 | GEO
Project description:Background: Antigen-specific T cells are particularly important for eliminating bacterial infection, and the dynamics in this process help uncover the mechanisms by which bacteria are eliminated.Results: In this study, we sorted the antigen-specific CD8+ T cell in the mouse liver and spleen at 5, 7, and 14 days after infection of Listeria monocytogenes expressing the OVA protein, finding that antigen-specific CD8+ T cell expansion after infection peaked on Day 7. Through the RNAseq analysis, we identified 355 genes whose expression peaked on 7 days post-infection shared in both of spleen and liver. For these shared genes, the KEGG pathway analysis showed a notable enrichment in the metabolic pathway. We also discovered 1621 proteins shared in the mouse liver and spleen that peaked seven days after infection by the LC-MS/MS analysis. The KEGG pathway analysis for these proteins revealed a significant enrichment in Splicesome, RNA transport, Ubiquitin mediated proteolysis, and Huntington disease. Transcriptomics coupled proteomics reveals 45 genes/proteins that were elevated on day 7 post listeria infection both in the spleen and liver. These 45 molecules were enriched in Human T-cell leukemia virus 1 infection and T cell activation, which played an important role in the activation of T cells and the anti-infection process.Conclusion: Transcriptomics coupled proteomics reveals the key signaling pathways to regulate antigen-specific CD8+ T cells by infection of Listeria monocytogenes expressing the OVA protein in mouse spleen and liver.
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