Designed neopeptides activate antitumor immune response
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ABSTRACT:
PROVIDER: PRJEB56517 | ENA |
REPOSITORIES: ENA
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Project description:Designed neopeptides activate antitumor immune response
| PRJEB56507 | ENA
Project description:<p>Blockade of T cell coinhibitory molecules such as CTLA-4 and PD-1, can activate T cell antitumor response. Although these immune checkpoint blockades (CTLA-4 blockade and PD-1 blockade) have shown durable response, response rate is modest. Therefore, there is a need to find stable biomarkers predictive of response to immune checkpoint blockades and to understand underlying resistance mechanisms. We collected longitudinal tumor biopsies from a cohort of metastatic melanoma patients treated with sequential immune checkpoint blockades and performed whole exome sequencing of this cohort. The comprehensive genomic characterization of tumors enabled identification of higher copy number loss burden as a resistance mechanism and clonal T cell repertoire as a predictive biomarker.</p>
| phs001425 | dbGaP
Project description:Adoptively transferred T cells and agents designed to block the CD47/SIRPalpha axis are promising cancer therapeutics that activate distinct arms of the immune system. We administered anti-CD47 with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which abrogated therapeutic benefit. anti-CD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPalpha and provided a “don’t-eat-me” signal that was not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following anti-CD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests enhanced potency against solid tumors.
2024-03-13 | GSE261475 | GEO
Project description:Cellular senescence is a stress response known to activate innate immunity. However, how senescent cells interact with the adaptive immune system remains largely unexplored. Here, we show that senescent cells display an enhanced MHC class I antigen processing and presentation. Furthermore, senescent cells present an altered immunopeptidome including unique non-mutated antigens that can be recognized by specific CD8 T cells. Immunization of mice with senescent cancer cells triggers strong protective CD8-dependent antitumor responses, superior to immunogenic cell death. Similarly, induction of senescence in human primary cancer cells hyperactivates their cognate reactive CD8 T cell. Our study indicates that immunization with senescent cells provides a sustained source of antigens that strongly activate anti-tumor CD8 T cells.
2022-10-18 | PXD033714 | Pride
Project description:Targeting Type I arginine methyltransferase PRMT1 promotes the T cell mediated antitumor immune response
| PRJNA682604 | ENA
Project description:A plant immune protein enables broad antitumor response by rescuing microRNA deficiency in cancers
| PRJNA813858 | ENA
Project description:Cancer cells are featured with uncontrollable activation of cell cycle and proliferation,and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small RNA-mediated immune response in plants, but absent in vertebrates with adaptive immunity. Here we show that ectopic expression of plant RDR1 can generally inhibit the proliferation of different cancer cells. Interestingly, we find that abnormal AGO2-free microRNA isoforms with 1-nucleotide shortening at the 3’ end are widely accumulated in many tumors. RDR1 with nucleotidyltransferase activity can recognize and modify these problematic microRNAs with mononucleotides to restore their AGO2 loading efficiency, which eventually rescues microRNA deficiency and elevates microRNA expression to target cell cycle in cancer specifically. The wide antitumor effects of RDR1 can be visualized in multiple xenograft tumor models in vivo, which can be realized by adeno-associated virus-mediated delivery. Altogether, we develop a broad microRNA-mediated antitumor stratagem using the plant immune protein RDR1.
2022-03-08 | GSE198146 | GEO
Project description:Cancer cells are featured with uncontrollable activation of cell cycle and proliferation,and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small RNA-mediated immune response in plants, but absent in vertebrates with adaptive immunity. Here we show that ectopic expression of plant RDR1 can generally inhibit the proliferation of different cancer cells. Interestingly, we find that abnormal AGO2-free microRNA isoforms with 1-nucleotide shortening at the 3’ end are widely accumulated in many tumors. RDR1 with nucleotidyltransferase activity can recognize and modify these problematic microRNAs with mononucleotides to restore their AGO2 loading efficiency, which eventually rescues microRNA deficiency and elevates microRNA expression to target cell cycle in cancer specifically. The wide antitumor effects of RDR1 can be visualized in multiple xenograft tumor models in vivo, which can be realized by adeno-associated virus-mediated delivery. Altogether, we develop a broad microRNA-mediated antitumor stratagem using the plant immune protein RDR1.
2022-03-08 | GSE198145 | GEO
Project description:To examine the immune responses that occur in Brca1-deficent tumors upon olaparib treatment, we performed gene expression analysis of a panel of 4604 cancer and immune-related genes in tumor tissues harvested from Brca1-deficient ovarian tumor-bearing mice after treatment with olaparib or vehicle. Transcriptome analysis showed that the expression of genes associated with immune response, T-cell activation and interferon-gamma(IFNgamma) response were markedly upregulated in tumors treated with olaparib as compared to vehicle. Our data reveal the antitumor immune response of PARP inhibition and demonstrate that it contributes to therapeutic efficacy of PARP inhibition in Brca1-deficient tumors.
2019-02-13 | GSE120500 | GEO
Project description:Macrophages play a crucial role in shaping the immune state within tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs towards an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications.
2023-09-19 | GSE243210 | GEO