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Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB\n                    <jats:sup>+<\/jats:sup>\n                    cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ado8275","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T13:58:32Z","timestamp":1730296712000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8067-9318","authenticated-orcid":true,"given":"Qiang","family":"Shen","sequence":"first","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3346-0376","authenticated-orcid":true,"given":"Kiichi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Sotov","sequence":"additional","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9840-7057","authenticated-orcid":true,"given":"Marcus","family":"Butler","sequence":"additional","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."},{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada."},{"name":"Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2915-9317","authenticated-orcid":true,"given":"Pamela S.","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."},{"name":"Department of Immunology, University of Toronto, Medical Sciences Building, 1 King\u2019s College Circle, Room 7205, Toronto, Ontario M5S 1A8, Canada."},{"name":"Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Room 15-701, Toronto, Ontario M5G 2M9, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4305-723X","authenticated-orcid":true,"given":"Michael","family":"Reedijk","sequence":"additional","affiliation":[{"name":"Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada."},{"name":"Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Room 15-701, Toronto, Ontario M5G 2M9, Canada."},{"name":"Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Suite 8-411, Toronto, Ontario M5G 2M9, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29210"},{"key":"e_1_3_2_3_2","unstructured":"A. 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