{"doi":"10.1667/rade-20-00237.1","title":"Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain","abstract":"Brain metastases develop in over 60% of advanced melanoma patients and negatively impact quality of life and prognosis. In a murine melanoma model, we previously showed that an in situ vaccination (ISV) regimen, combining radiation treatment and intratumoral (IT) injection of immunocytokine (IC: anti-GD2 antibody fused to IL2), along with the immune checkpoint inhibitor anti-CTLA-4, robustly eliminates peripheral flank tumors but only has modest effects on co-occurring intracranial tumors. In this study, we investigated the ability of low-dose radiation to the brain to potentiate anti-tumor immunity against a brain tumor when combined with ISV + anti-CTLA-4. B78 (GD2+, immunologically \"cold\") melanoma tumor cells were implanted into the flank and the right striatum of the brain in C57BL/6 mice. Flank tumors (50-150 mm3) were treated following a previously optimized ISV regimen [radiation (12 Gy × 1, treatment day 1), IT-IC (50 µg daily, treatment days 6-10), and anti-CTLA-4 (100 µg, treatment days 3, 6, 9)]. Mice that additionally received whole-brain radiation treatment (WBRT, 4 Gy × 1) on day 15 demonstrated significantly increased survival compared to animals that received ISV + anti-CTLA-4 alone, WBRT alone or no treatment (control) (P < 0.001, log-rank test). Timing of WBRT was critical, as WBRT administration on day 1 did not significantly enhance survival compared to ISV + anti-CTLA-4, suggesting that the effect of WBRT on survival might be mediated through immune modulation and not just direct tumor cell cytotoxicity. Modest increases in T cells (CD8+ and CD4+) and monocytes/macrophages (F4/80+) but no changes in FOXP3+ regulatory T cells (Tregs), were observed in brain melanoma tumors with addition of WBRT (on day 15) to ISV + anti-CTLA-4. Cytokine multiplex immunoassay revealed distinct changes in both intracranial melanoma and contralateral normal brain with addition of WBRT (day 15) to ISV + anti-CTLA-4, with notable significant changes in pro-inflammatory (e.g., IFNγ, TNFα and LIX/CXCL5) and suppressive (e.g., IL10, IL13) cytokines as well as chemokines (e.g., IP-10/CXCL10 and MIG/CXCL9). We tested the ability of the alkylphosphocholine analog, NM600, to deliver immunomodulatory radiation to melanoma brain tumors as a targeted radionuclide therapy (TRT). Yttrium-86 (86Y) chelated to NM600 was delivered intravenously by tail vein to mice harboring flank and brain melanoma tumors, and PET imaging demonstrated specific accumulation up to 72 h at each tumor site (∼12:1 brain tumor/brain and ∼8:1 flank tumor/muscle). When NM600 was chelated to therapeutic β-particle-emitting 90Y and administered on treatment day 13, T-cell infiltration and cytokine profiles were altered in melanoma brain tumor, like that observed for WBRT. Overall, our results demonstrate that addition of low-dose radiation, timed appropriately with ISV administration to tumors outside the brain, significantly increases survival in animals co-harboring melanoma brain tumors. This observation has potentially important translational implications as a treatment strategy for increasing the response of tumors in the brain to systemically administered immunotherapies.","journal":"Radiation Research","year":2021,"id":176228,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":339891,"name":"Raghava N. Sriramaneni","orcid":"0000-0002-9452-8708","position":1,"is_corresponding":false},{"id":339892,"name":"Amber M. Bates","orcid":"0000-0002-5184-4532","position":2,"is_corresponding":false},{"id":339888,"name":"Won Jong Jin","orcid":"0000-0003-4147-9735","position":3,"is_corresponding":false},{"id":259500,"name":"Justin C. Jagodinsky","orcid":"0000-0002-6204-4899","position":4,"is_corresponding":false},{"id":621689,"name":"Reinier Hernandez","orcid":"0000-0002-0729-2179","position":5,"is_corresponding":false},{"id":339894,"name":"Trаng Lе","orcid":"0009-0008-9148-2848","position":6,"is_corresponding":false},{"id":718756,"name":"Justin J. Jeffery","orcid":null,"position":7,"is_corresponding":false},{"id":621690,"name":"Ian R. Marsh","orcid":"0000-0002-0031-9746","position":8,"is_corresponding":false},{"id":514910,"name":"Joseph J. Grudzinski","orcid":"0000-0002-8799-1649","position":9,"is_corresponding":false},{"id":402471,"name":"Eduardo Aluicio‐Sarduy","orcid":"0000-0002-7889-9162","position":10,"is_corresponding":false},{"id":244586,"name":"Todd E. Barnhart","orcid":"0000-0002-9981-2150","position":11,"is_corresponding":false},{"id":340937,"name":"Bryce R. Anderson","orcid":null,"position":12,"is_corresponding":false},{"id":421349,"name":"Ishan Chakravarty","orcid":null,"position":13,"is_corresponding":false},{"id":420381,"name":"Ian S. Arthur","orcid":"0000-0002-3927-3570","position":14,"is_corresponding":false},{"id":266922,"name":"KyungMann Kim","orcid":"0000-0002-6726-003X","position":15,"is_corresponding":false},{"id":244590,"name":"Jonathan W. Engle","orcid":"0000-0002-3399-7228","position":16,"is_corresponding":false},{"id":451106,"name":"Bryan P. Bednarz","orcid":"0000-0002-7467-9816","position":17,"is_corresponding":false},{"id":621691,"name":"Jamey P. Weichert","orcid":"0000-0002-2048-6381","position":18,"is_corresponding":false},{"id":259502,"name":"Zachary S. Morris","orcid":"0000-0001-5558-3547","position":19,"is_corresponding":false},{"id":339893,"name":"Paul A. Clark","orcid":"0000-0002-1608-1146","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-18T23:47:19.591542Z","pmid":"33826741","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":[]}