{"doi":"10.1101/2023.08.14.553229","title":"Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression","abstract":"Abstract Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (T reg ). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced T reg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB. Brief Summary Immune therapy has been disappointing for breast cancer. NR0B2 within myeloid immune cells reduces the expansion of T regs , a highly immune suppressive subtype historically challenging to target. NR0B2 within myeloid immune cells represses the inflammasome, leading to reduced T reg expansion and subsequent tumor growth/metastasis. Activation of NR0B2 with small molecule agonists, including one developed herein, attenuates tumor growth and metastasis in murine models of mammary cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":410389,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":284354,"name":"Sayyed Hamed Shahoei","orcid":"0009-0001-0625-2677","position":1,"is_corresponding":false},{"id":1190728,"name":"Samuel T. 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