{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T19:15:33Z","timestamp":1771355733594,"version":"3.50.1"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA281285"],"award-info":[{"award-number":["R01CA281285"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47\/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent\/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of an anti-CD47 fusion protein in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. In the 4MOSC1 syngeneic HPV-negative HNSCC mouse model, ALX301 (an engineered CD47-blocking SIRP\u03b1 fusion for murine models) induced complete tumor regression when combined with anti\u2013PD-1, and produced a partial tumor response as a monotherapy. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. ALX301 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8\u2009+\u2009T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of ALX301 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.<\/jats:p>","DOI":"10.1371\/journal.pone.0328031","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T18:29:51Z","timestamp":1771352991000},"page":"e0328031","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD47 blockade (ALX301) enhances immunoradiotherapy response in HPV negative head and neck squamous cell carcinoma"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0822-3882","authenticated-orcid":true,"given":"Abdula","family":"Monther","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riyam","family":"Al-Msari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Saddawi-Konefka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago","family":"Fassardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad","family":"Philips","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prakriti","family":"Sen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pardis","family":"Mohammadzadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey","family":"Decker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8439-7751","authenticated-orcid":true,"given":"Sayuri","family":"Miyauchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0411-1221","authenticated-orcid":true,"given":"Souvick","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-4699","authenticated-orcid":true,"given":"Riley","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvio","family":"Gutkind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Sharabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-6761","authenticated-orcid":true,"given":"Joseph","family":"Califano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"issue":"1","key":"pone.0328031.ref001","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1056\/NEJMra1715715","article-title":"Head 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