{"doi":"10.1101/2024.07.18.603996","title":"γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.</jats:p>","journal":null,"year":null,"id":631032,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1635083,"name":"Sravya Palasalava","orcid":null,"position":1,"is_corresponding":false},{"id":1390365,"name":"Maxon V. 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Wong","orcid":null,"position":8,"is_corresponding":false},{"id":440096,"name":"Li Zhang","orcid":"0000-0003-0006-4066","position":9,"is_corresponding":false},{"id":1635090,"name":"Nikola Susic","orcid":null,"position":10,"is_corresponding":false},{"id":1635091,"name":"Khushi Hemendra Shah","orcid":null,"position":11,"is_corresponding":false},{"id":433809,"name":"Kristen Kay","orcid":"0000-0002-4459-6454","position":12,"is_corresponding":false},{"id":1016661,"name":"Diana Chin","orcid":"0000-0002-1645-3552","position":13,"is_corresponding":false},{"id":564964,"name":"Sadie Johnson","orcid":"0000-0001-5250-9835","position":14,"is_corresponding":false},{"id":69831,"name":"Feixiong Cheng","orcid":"0000-0002-1736-2847","position":15,"is_corresponding":false},{"id":106351,"name":"Costas A. Lyssiotis","orcid":"0000-0001-9309-6141","position":16,"is_corresponding":false},{"id":240683,"name":"Dionysios C. Watson","orcid":"0000-0002-9146-5641","position":17,"is_corresponding":false},{"id":51794,"name":"Michele Ceccarelli","orcid":null,"position":18,"is_corresponding":false},{"id":1300895,"name":"Ashish Shah","orcid":"0000-0003-0817-5940","position":19,"is_corresponding":false},{"id":1635092,"name":"Daniel R. Wahl","orcid":null,"position":20,"is_corresponding":false},{"id":240691,"name":"Justin D. Lathia","orcid":"0000-0003-3168-7290","position":21,"is_corresponding":false},{"id":1635093,"name":"Defne Bayik","orcid":null,"position":22,"is_corresponding":false},{"id":397065,"name":"Asmita Pathak","orcid":"0009-0006-5955-1714","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.</jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39091833","pmcid":null,"openalex_id":"https://openalex.org/W4400931908","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"5R00CA277242-04","title":"Mitochondrial transfer from astrocytes to glioblastoma cells drives tumor growth"},{"funder_name":"National Institutes of Health","grant_id":"1R35NS127083-01","title":"Contribution of Myeloid-Derived Suppressor Cells to Neuro-Inflammatory Alterations and Disease Progression in Glioblastoma"},{"funder_name":"National Institutes of Health","grant_id":"5K08CA234416-05","title":"De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in Glioblastoma"},{"funder_name":"National Institutes of Health","grant_id":"3P30CA240139-02S3","title":"The Sylvester Cancer Center Support Grant"},{"funder_name":"National Institutes of Health","grant_id":"5R37CA258346-03","title":"Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma"},{"funder_name":"National Institutes of Health","grant_id":"5R00CA248611-04","title":"Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma"},{"funder_name":"National Institutes of Health","grant_id":"5F31CA264849-03","title":"Polyamines drive glioblastoma progression"},{"funder_name":"National Institutes of Health","grant_id":"5P01CA245705-02","title":"Sex-based Differences in Glioma"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS129123-03","title":"Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma."},{"funder_name":"NCI NIH HHS","grant_id":"R00 CA248611","title":null},{"funder_name":"NCI NIH HHS","grant_id":"F31 CA264849","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R37 CA258346","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P50 CA269022","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS129123","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R35 NS127083","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA245705","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA240139","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R00 CA277242","title":null},{"funder_name":"NCI NIH HHS","grant_id":"K08 CA234416","title":null}],"total_grants":19,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2025,"count":3}],"oa_status":"green","license":"cc-by-nc","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/07/22/2024.07.18.603996.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2024/07/22/2024.07.18.603996.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.07.18.603996","host_type":"publisher"},{"url":"https://doi.org/10.1101/2024.07.18.603996","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39091833","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11291093","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11291093/pdf/nihpp-2024.07.18.603996v1.pdf","host_type":"repository"},{"url":"https://doi.org/10.21203/rs.3.rs-4790899/v1","host_type":""},{"url":"http://dx.doi.org/10.1101/2024.07.18.603996","host_type":""}],"fields_of_study":["Cancer, Stress, Anesthesia, and Immune Response","Immunotherapy and Immune Responses","Neuroinflammation and Neurodegeneration Mechanisms","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":[],"keywords":["Glioblastoma","Immune system","Receptor","Biology","Neuroscience","Cell biology","Chemistry","Cancer research","Immunology","Genetics","Article","GABA","L-arginine","myeloid-derived suppressor cells","nitric oxide synthase 2","sex differences"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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