{ "abstract": "Background: GIST tumor microenvironment is characterized by an abundant immune infiltrate. Imatinib exerts immunomodulatory effects that may contribute to a more immunosuppressive microenvironment. Nonetheless, checkpoint inhibitors have demonstrated limited efficacy to date supporting the rationale for combination strategies integrating immunotherapy and TKIs to enhance anti-tumor immune response. This study aims to identify immunological predictive biomarkers and to establish a rational framework for a personalized immunotherapeutic strategy capable of synergizing with TKIs in advanced GIST.\n\nMaterials and methods: We performed an integrated immune profiling of 49 KIT-PDGFRA -mutant GIST samples. Multiplexed immunohistochemistry was used to quantify innate and adaptive immune populations, regulatory subsets, immune checkpoint expression, HLA class I/II status. Immune features were assessed by digital pathology and analyzed according to genotype, site, primary versus metastatic disease, TKI exposure. In a subset of tumors, bulk RNA sequencing and CIBERSORTx deconvolution were used to complement tissue-based immune characterization.\n\nResults: GISTs displayed a heterogeneous but consistently immune-infiltrated microenvironment enriched in CD163-positive M2-like tumor-associated macrophages. T cells represented the second largest immune population and included both CD8+ and CD4+ T cells. NK cells were also detectable, whereas B cells and regulatory T cells were generally less abundant. CTLA-4 expression was widespread but low, whereas tumor-cell PD-L1 expression was highly variable. Notably, complete or subclonal HLA class I loss was identified in 20% of tumors. PDGFRA -mutant GISTs showed a significantly inflamed profile, with increased B and T lymphocytes and NK cells. Intestinal GISTs exhibited higher infiltration by T-cell, NK and macrophage populations than gastric tumors. In KIT -mutant primary tumors, imatinib exposure markedly reshaped the immune microenvironment, reducing regulatory T cells, NK cells and CD68/CD163-positive macrophages while relatively preserving CD8-positive T cells.\n\nConclusions: GISTs harbor a rich and heterogeneous immune microenvironment shaped by genotype, site, TKI exposure, antigen-presentation status. The complete or subclonal HLA-I loss as a potential immune escape mechanism, a more lymphoid-, B-cell-, and NK-enriched immune profile in PDGFRA -mutant tumors, the site-specific immune enrichment of intestinal GISTs, and the selective remodeling of regulatory and myeloid immune compartments after imatinib refine the current understanding of GIST immunobiology and support the development of rational, biomarker-driven immunotherapeutic strategies.", "abstract_shown": true, "affiliations": [ "IRCCS Azienda Ospedaliero-Universitaria di Bologna", "Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna", "Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna", "Department of Medical and Surgical Sciences (DIMEC), University of Bologna", "General Surgery and Transplant Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna" ], "article_type": "research article", "arxiv": null, "author_total": 14, "authors": [ { "affs": [ 0 ], "name": "Alice Costa" }, { "affs": [ 1 ], "name": "Maria Concetta Nigro" }, { "affs": [ 2, 3 ], "name": "Marco Grillini" }, { "affs": [ 3 ], "name": "Livia Gozzellino" }, { "affs": [ 3 ], "name": "Margherita Nannini" }, { "affs": [ 3 ], "name": "Ilenia Motta" }, { "affs": [ 2, 3 ], "name": "Antonio De Leo" }, { "affs": [ 2 ], "name": "Maria Giulia Pirini" }, { "affs": [ 4 ], "name": "Massimo Del Gaudio" }, { "affs": [ 3 ], "name": "Matteo Ravaioli" }, { "affs": [ 0 ], "name": "Manuela Ianni" }, { "affs": [ 3 ], "name": "Gianandrea Pasquinelli" }, { "affs": [ 0, 3 ], "name": "Annalisa Astolfi" }, { "affs": [ 3 ], "name": "Maria Abbondanza Pantaleo" } ], "bibtex": "https://research.draconitic.com/paper/1t0e7tej1zd40.bib", "cited_by": 0, "doi": "10.3389/fimmu.2026.1961524", "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717502/?tool=EBI", "id": "1t0e7tej1zd40", "issns": [ "1664-3224" ], "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961524/full", "language": "eng", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Original Research" ], [ "openalex", "2715|Gastrointestinal Tumor Research and Treatment" ] ], "openalex": "W7221993937", "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1961524/pdf", "pmcid": "PMC13717502", "pmid": "42959738", "published": "2026-10-15", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/1t0e7tej1zd40.ris", "sources": [ { "first_seen": "2026-10-30T12:19:17Z", "native_id": "10.3389/fimmu.2026.1961524", "source": "crossref", "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961524/full" }, { "first_seen": "2026-10-31T00:20:37Z", "native_id": "PMC:PMC13717502", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13717502" }, { "first_seen": "2026-11-01T00:20:52Z", "native_id": "MED:42959738", "source": "europepmc", "url": "https://europepmc.org/article/MED/42959738" }, { "first_seen": "2026-11-02T12:21:48Z", "native_id": "PMC13717502", "source": "pmc", "url": "https://doi.org/10.3389/fimmu.2026.1961524" } ], "subjects": [ { "field": "biology", "origin": "issn:1664-3224", "subfield": "immunology" } ], "title": "Mapping the immune microenvironment of KIT- and PDGFRA-mutant GISTs reveals genotype-specific immune infiltration and TKI-induced remodeling", "title_text": "Mapping the immune microenvironment of KIT- and PDGFRA-mutant GISTs reveals genotype-specific immune infiltration and TKI-induced remodeling", "type": "peer-reviewed", "updated_at": "2026-11-02T12:21:48Z", "url": "https://research.draconitic.com/paper/1t0e7tej1zd40", "venue": "Frontiers in Immunology", "versions": [] }