{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T11:37:20Z","timestamp":1786621040120,"version":"build-2736575974"},"reference-count":67,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"unspecified","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"The Nancy L. De Anda Research Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"MDACC Institutional Research Grant","award":["600382-30-123531-21"],"award-info":[{"award-number":["600382-30-123531-21"]}]},{"name":"National Institute of Health","award":["5R01DE030875"],"award-info":[{"award-number":["5R01DE030875"]}]},{"name":"National Institute of Health","award":["5U01DE028233-03"],"award-info":[{"award-number":["5U01DE028233-03"]}]},{"DOI":"10.13039\/100001538","name":"Mary K Chapman Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001538","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,27]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunotherapeutic approaches for cutaneous squamous cell carcinoma (cSCC) remain limited to programmed cell death protein 1 (PD-1) blockade. Although genomics studies have characterized key driver mutations in cSCC, preclinical models that faithfully recapitulate both the genetic landscape and immune microenvironment of the human disease, that could drive the development of novel, effective therapies, are lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To address this need, we generated genetically engineered mouse models harboring inducible\n                      <jats:italic>p53<\/jats:italic>\n                      wmR172H expression and\n                      <jats:italic>Cdkn2a<\/jats:italic>\n                      deletion in stratified epithelia. These mice spontaneously developed well-differentiated and spindle cell cSCCs, whose histopathological and immunological features mimicked those observed in patients. We established syngeneic cell lines and characterized their genomic and transcriptomic profiles through whole exome sequencing and RNA sequencing. We used these syngeneic tumor models to test the effect of STING agonist, PD-1, VISTA and CTLA-4 blockade applied at different schedules and combinations. Finally, immune checkpoint molecules detected in the syngeneic models were validated in human cSCC tissue arrays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Whole exome sequencing confirmed alterations overlapping with human cSCC, including mutations in\n                      <jats:italic>Notch<\/jats:italic>\n                      , interferon signaling, and cytokine pathways. Transcriptomic analysis revealed the upregulation of immunoregulatory genes, including\n                      <jats:italic>Cd274<\/jats:italic>\n                      ,\n                      <jats:italic>Lgals9<\/jats:italic>\n                      , and\n                      <jats:italic>Il33<\/jats:italic>\n                      , suggesting a suppressive tumor immune microenvironment (TIME). Preclinical therapeutic evaluation in this model demonstrated that PD-1 blockade and the treatment with a STING agonist elicited partial responses. The combination of STING agonist with checkpoint inhibition targeting either PD-1\/CTLA-4 or PD-1\/VISTA significantly enhanced antitumor immunity in tumors resistant to anti-PD-1 monotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results establish a robust, genetically defined, immunocompetent platform for modeling cSCC and evaluating novel immunotherapeutic strategies for treating patients with this disease. Our findings also identify VISTA and CTLA-4 as promising immune checkpoints to target in cSCC and support clinical evaluation of this combination of immune checkpoint blockade to overcome immune checkpoint inhibitor resistance and improve clinical outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013976","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T11:10:40Z","timestamp":1786619440000},"page":"e013976","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Development of an immunocompetent cutaneous squamous cell carcinoma model identifies VISTA and CTLA-4 as targetable immune checkpoints"],"prefix":"10.1136","volume":"14","author":[{"given":"Alanis E","family":"Rodriguez Rosario","sequence":"first","affiliation":[{"name":"University of Puerto Rico School of Medicine, San Juan, Puerto Rico"},{"name":"Department of Head and Neck Surgery, The University 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Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-8818","authenticated-orcid":false,"given":"Ricardo M","family":"Cruz Sanchez","sequence":"additional","affiliation":[{"name":"University of Puerto Rico School of Medicine, San Juan, Puerto Rico"},{"name":"Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemalene M","family":"Sunga","sequence":"additional","affiliation":[{"name":"University of Puerto Rico School of Medicine, San Juan, Puerto Rico"},{"name":"Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA"},{"name":"Katz Department of Oral and maxillofacial Surgery, The University of Texas Health Science Center at Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratna","family":"Veeramachaneni","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganiraju C","family":"Manyam","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pathology Anatomical, The University of Texas MD Anderson 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