{"doi":"10.4049/jimmunol.2300326","title":"Dose-Specific Intratumoral GM-CSF Modulates Breast Tumor Oxygenation and Antitumor Immunity","abstract":"GM-CSF has been employed as an adjuvant to cancer immunotherapy with mixed results based on dosage. We previously showed that GM-CSF regulated tumor angiogenesis by stimulating soluble vascular endothelial growth factor (VEGF) receptor-1 from monocytes/macrophages in a dose-dependent manner that neutralized free VEGF, and intratumoral injections of high-dose GM-CSF ablated blood vessels and worsened hypoxia in orthotopic polyoma middle T Ag (PyMT) triple-negative breast cancer (TNBC). In this study, we assessed both immunoregulatory and oxygen-regulatory components of low-dose versus high-dose GM-CSF to compare effects on tumor oxygen, vasculature, and antitumor immunity. We performed intratumoral injections of low-dose GM-CSF or saline controls for 3 wk in FVB/N PyMT TNBC. Low-dose GM-CSF uniquely reduced tumor hypoxia and normalized tumor vasculature by increasing NG2+ pericyte coverage on CD31+ endothelial cells. Priming of \"cold,\" anti-PD1-resistant PyMT tumors with low-dose GM-CSF (hypoxia reduced) sensitized tumors to anti-PD1, whereas high-dose GM-CSF (hypoxia exacerbated) did not. Low-dose GM-CSF reduced hypoxic and inflammatory tumor-associated macrophage (TAM) transcriptional profiles; however, no phenotypic modulation of TAMs or tumor-infiltrating lymphocytes were observed by flow cytometry. In contrast, high-dose GM-CSF priming increased infiltration of TAMs lacking the MHC class IIhi phenotype or immunostimulatory marker expression, indicating an immunosuppressive phenotype under hypoxia. However, in anti-PD1 (programmed cell death 1)-susceptible BALB/c 4T1 tumors (considered hot versus PyMT), high-dose GM-CSF increased MHC class IIhi TAMs and immunostimulatory molecules, suggesting disparate effects of high-dose GM-CSF across PyMT versus 4T1 TNBC models. Our data demonstrate a (to our knowledge) novel role for low-dose GM-CSF in reducing tumor hypoxia for synergy with anti-PD1 and highlight why dosage and setting of GM-CSF in cancer immunotherapy regimens require careful consideration.","journal":"The Journal of Immunology","year":2023,"id":343326,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":430903,"name":"Kayla J. Steinberger","orcid":"0000-0002-2882-8593","position":1,"is_corresponding":false},{"id":333087,"name":"Alyson M. Stevens","orcid":null,"position":2,"is_corresponding":false},{"id":430904,"name":"Andrey A. Bobko","orcid":"0000-0003-1576-5236","position":3,"is_corresponding":false},{"id":431543,"name":"E. Hannah Hoblitzell","orcid":null,"position":4,"is_corresponding":false},{"id":514471,"name":"Oxana Tseytlin","orcid":"0000-0001-9078-175X","position":5,"is_corresponding":false},{"id":871176,"name":"Halima Akhter","orcid":"0000-0002-5687-3578","position":6,"is_corresponding":false},{"id":827112,"name":"Sebastian A. Dziadowicz","orcid":"0000-0001-6277-9310","position":7,"is_corresponding":false},{"id":1080851,"name":"Lei Wang","orcid":"0000-0002-3625-506X","position":8,"is_corresponding":false},{"id":952181,"name":"Ryan C. O’Connell","orcid":"0000-0003-0945-3631","position":9,"is_corresponding":false},{"id":477628,"name":"Kelly L. Monaghan","orcid":"0000-0002-3298-8485","position":10,"is_corresponding":false},{"id":331852,"name":"Gangqing Hu","orcid":"0000-0001-5453-6888","position":11,"is_corresponding":false},{"id":232152,"name":"Xiaokui Mo","orcid":"0000-0002-9797-2687","position":12,"is_corresponding":false},{"id":430911,"name":"Valery V. Khramtsov","orcid":"0000-0001-6187-5546","position":13,"is_corresponding":false},{"id":1080852,"name":"Mark Tseytlin","orcid":"0000-0001-6273-0533","position":14,"is_corresponding":false},{"id":383933,"name":"Benoît Driesschaert","orcid":"0000-0002-1402-413X","position":15,"is_corresponding":false},{"id":379415,"name":"Chi‐Keung Wan","orcid":"0000-0003-4783-3029","position":16,"is_corresponding":false},{"id":430912,"name":"Timothy D. Eubank","orcid":"0000-0002-8225-7824","position":17,"is_corresponding":false},{"id":430905,"name":"Nicole E. Mihalik","orcid":"0000-0002-8220-6613","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T01:11:21.758449Z","pmid":"37756529","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}