Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1072155 | ENA |
REPOSITORIES: ENA
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Project description:Tumor microenvironment-activated angiotensin blockers enhance cancer immunotherapy
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Project description:T-cell immune checkpoint inhibitors have revolutionized cancer immunotherapy. In addition to T cells, immune checkpoint molecules have also been described for myeloid cells, with CD47 on tumor cells and Signal Regulatory Protein α (SIRPα) on effector cells being the most established example (Maute et al. Immunooncol Technol. 2022). Blockade of this checkpoint by CD47 or SIRPα targeting molecules has been demonstrated to enhance the efficacy of therapeutic antibodies in many preclinical tumor models (Müller et al. Blood. 2022, Schewe et al. Hemasphere. 2024). Next to CD47/SIRPα blocking molecules, inhibition of Glutaminyl-Peptide Cyclotransferase-Like (QPCTL) - the enzyme that catalyzes functionally relevant pyroglutamate (pGlu) formation on many peptides and proteins including CD47 - was shown to modify the myeloid tumor cell infiltrate (Barreira et al. Nat Immunol. 2022) and to improve antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against tumor cells (Logtenberg et al. Nat Med. 2019, Wu et al. Cell Res. 2019, Baumann et al. Front Immunol. 2021). Crystallographic analyses of CD47 in complex with SIRPα revealed that the CD47 binding pocket for SIRPα contains pGlu at the N-terminus (Hatherley et al. Mol Cell. 2008). However, on cellular level the direct involvement of pGlu in the CD47/SIRPα interaction has not been confirmed yet. We generated human CD47 Fc proteins, that contain either a native CD47 ectodomain with N-terminal pGlu (CD47-wt) or a mutated version with alanine at the N-terminus (CD47-Q1A), which was confirmed by mass spectrometry. Differential binding of CD47-wt and CD47-Q1A revealed that pGlu on CD47 is essential for binding to SIRPα on macrophages, supporting that inhibition of QPCTL is a good therapeutic option for enhanced tumor cell killing through CD47/SIRPα interference.
2026-05-19 | PXD066444 | Pride
Project description:Lysine metabolism reprogramming reshapes the immune microenvironment and induces immunotherapy tolerance in liver cancer
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Project description:USP2 inhibition by ML364 treatment significantlly suppressed tumor growth. We aim to investigate the impact of ML364 treatment on the immune microenvironment of tumor-bearing mice by single-cell sequencing.
2025-04-03 | GSE254966 | GEO
Project description:The field of immunotherapy for clear cell renal cell carcinoma (ccRCC) is rapidly expanding over the past decade, but limited success to date. Cancer cell-intrinsic features (e.g., genetic aberrations, dysregulation of signaling pathway) play a pivotal role in orchestrating the composition and functional state of immune landscape, which in turn impact tumor progression and response to immunotherapy. However, the underlying mechanism of crosstalk between renal cancer cell and immune cell is largely unknown. Here we discovered that cancer cell-intrinsic SET and MYND domain-containing protein 3 (SMYD3) dysregulation orchestrated an immunosuppressive microenvironment and impaired responses to PD-1 blockade by reprograming the infiltration of immune cells in tumor microenvironment (TME) of ccRCC. Mechanistically, SMYD3, a chromatin regulator, cooperated with Sp1 to transcriptionally promote sterol regulatory element-binding protein 1 (SREBP1) expression by modifying H3-K4 di-/trimethylation and consequently activating the transcription of CD47. CD47, a bridge between innate and adaptive immunity, acted as the downstream effector molecule of the SMYD3 signal to promote the infiltration of Th2 cells, protecting renal cancer cell from immune attack. In summary, we elucidated a critical role for cancer cell-intrinsic SMYD3-SREBP1-CD47 signal in the regulation of the immune microenvironment in ccRCC, and provided a potential strategy to manipulate the tumor immune milieu in favor of antitumor immunity.
2026-03-15 | GSE261853 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE186382 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE161178 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and it’s co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE161177 | GEO
Project description:In melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T cell non-inflamed tumors (‘cold tumors’) are associated with tumor cell intrinsic Wnt/β-catenin activation, and are resistant to anti-PD-1 alone or in combination with anti-CTLA-4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges in melanoma. In a well-established preclinical melanoma model driven by β-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials.
2023-10-30 | GSE155394 | GEO