{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T08:13:18Z","timestamp":1776154398418,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Trillium Therapeutics (Canada)","award":["02"],"award-info":[{"award-number":["02"]}]},{"name":"Drs. Martin and Dorothy Spatz Charitable Foundation","award":["01"],"award-info":[{"award-number":["01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRP\u03b1Fc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-\u03b1, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-\u03b1 in exploiting these clinical benefits.<\/jats:p>","DOI":"10.3390\/cancers13235982","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T01:49:58Z","timestamp":1638150598000},"page":"5982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides"],"prefix":"10.3390","volume":"13","author":[{"given":"Tony T.","family":"Jiang","sequence":"first","affiliation":[{"name":"Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9847-7581","authenticated-orcid":false,"given":"Oleg","family":"Kruglov","sequence":"additional","affiliation":[{"name":"Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria H. Y.","family":"Lin","sequence":"additional","affiliation":[{"name":"Trillium Therapeutics Inc., Mississauga, ON L5L 1J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5395-0032","authenticated-orcid":false,"given":"Angela","family":"Minic","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Uger","sequence":"additional","affiliation":[{"name":"Trillium Therapeutics Inc., Mississauga, ON L5L 1J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Wong","sequence":"additional","affiliation":[{"name":"Trillium Therapeutics Inc., Mississauga, ON L5L 1J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaping","family":"Shou","sequence":"additional","affiliation":[{"name":"Trillium Therapeutics Inc., Mississauga, ON L5L 1J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1339-5710","authenticated-orcid":false,"given":"Oleg E.","family":"Akilov","sequence":"additional","affiliation":[{"name":"Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1182\/blood-2004-09-3502","article-title":"WHO-EORTC classification for cutaneous lymphomas","volume":"105","author":"Willemze","year":"2005","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1001\/archderm.139.7.857","article-title":"Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: Clinical prognostic factors and risk for disease progression","volume":"139","author":"Kim","year":"2003","journal-title":"Arch. 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