{
    "abstract": "Immune checkpoint inhibitors (ICIs) present clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. The lack of ICIs efficacy in GBM is attributed to the accumulation of tumor-reprogrammed glioma-associated myeloid cells (GAMs) that create a \"cold\" immunosuppressive tumor microenvironment (TME), impeding the infiltration and activation of effector T cells. GBM-derived \u03b1v\u03b23/\u03b1v\u03b25-integrin ligands, including SPP1, were shown to mediate the emergence of GAMs. We hypothesized that a combination strategy aiming to block the reprogramming of GAMs using a synthetic 7aaRGD peptide that targets SPP1/integrin signaling might overcome resistance to ICIs and reinvigorate anti-tumor immunity.\nMatrigel invasion assay was used to test the efficacy of 7aaRGD in glioma-microglia co-cultures. We determined the impact of 7aaRGD, administered as a monotherapy or combined with PD-1 blockade, on tumor growth, GAMs accumulation and phenotypes, arginase-1 levels and neovasculature in experimental gliomas. The effects of treatments on the tumor immune landscape were dissected using multiparameter flow cytometry, immunocytochemistry, cytokine profiling and RNA-seq analysis of sorted GAMs followed by CITE-seq based data deconvolution.\n7aaRGD efficiently blocked microglia-dependent invasion of human and mouse glioma cells in vitro. Intratumorally delivered 7aaRGD alone did not reduce tumor growth in orthotopic gliomas but prevented the emergence of immunosuppressive GAMs and led to normalization of peritumoral blood vessels. Combining 7aaRGD with anti-PD-1 antibody resulted in reduced tumor growth, with an increase in the number of proliferating, interferon-\u0263 producing CD8\nWe demonstrate that combining the blockade of SPP1/integrin signaling with ICIs modifies innate immunity and reinvigorates adaptive antitumor responses, which paves the way to improve immunotherapy outcomes in GBM.",
    "authors": [
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland. a.ellert@nencki.edu.pl.",
            "firstname": "Aleksandra",
            "initials": "A",
            "lastname": "Ellert-Miklaszewska"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Paulina",
            "initials": "P",
            "lastname": "Pilanc"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Katarzyna",
            "initials": "K",
            "lastname": "Poleszak"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Adria-Jaume",
            "initials": "AJ",
            "lastname": "Roura"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Salwador",
            "initials": "S",
            "lastname": "Cyranowski"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Mitrajit",
            "initials": "M",
            "lastname": "Ghosh"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Szymon",
            "initials": "S",
            "lastname": "Baluszek"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Maria",
            "initials": "M",
            "lastname": "Pasierbinska"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Bart\u0142omiej",
            "initials": "B",
            "lastname": "Gielniewski"
        },
        {
            "affiliation": "Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Julian",
            "initials": "J",
            "lastname": "Swatler"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Yuliana",
            "initials": "Y",
            "lastname": "Hovorova"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.",
            "firstname": "Kamil",
            "initials": "K",
            "lastname": "Wojnicki"
        },
        {
            "affiliation": "Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland. b.kaminska@nencki.edu.pl.",
            "firstname": "Bozena",
            "initials": "B",
            "lastname": "Kaminska"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2025. The Author(s).",
    "doi": "10.1186/s13046-025-03393-9",
    "journal": "Journal of experimental & clinical cancer research : CR",
    "keywords": [
        "Blocking peptide",
        "Glioma",
        "Glioma-associated macrophages",
        "Immunotherapy",
        "Integrins",
        "Tumor microenvironment"
    ],
    "methods": null,
    "publication_date": "2025-04-26",
    "pubmed_id": "40281508\n37595586\n32289269\n34185076\n32437507\n26546453\n36594466\n28292436\n26713745\n34571910\n26427514\n33608526\n36140392\n32913278\n29371595\n30742122\n31879345\n34083417\n31025274\n35078492\n24056773\n27041573\n30307407\n25580734\n39227950\n28394627\n33916607\n26918452\n29963047\n23104886\n32332754\n36640350\n35140215\n19617536\n34504786\n17107968\n24779345\n18495788\n38100351\n19830727\n35928554\n30300585\n26858199\n29429633\n31185212\n29399390\n32071302\n25658639\n36054938\n35016033\n33846258\n34021248\n38566128\n20616217\n33187910\n37647386\n37055532\n30742120\n30742119\n7688125\n11120881\n16775224\n36638785\n26973881\n21629292\n25584895\n19584855\n31099649\n29935312\n28073001\n34836966\n28338065\n33755340\n28115578\n38615026",
    "results": "7aaRGD efficiently blocked microglia-dependent invasion of human and mouse glioma cells in vitro. Intratumorally delivered 7aaRGD alone did not reduce tumor growth in orthotopic gliomas but prevented the emergence of immunosuppressive GAMs and led to normalization of peritumoral blood vessels. Combining 7aaRGD with anti-PD-1 antibody resulted in reduced tumor growth, with an increase in the number of proliferating, interferon-\u0263 producing CD8",
    "title": "7aaRGD - a novel SPP1/integrin signaling-blocking peptide reverses immunosuppression and improves anti-PD-1 immunotherapy outcomes in experimental gliomas.",
    "xml": "<Element 'PubmedArticle' at 0x788502419fd0>"
}