{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T10:18:05Z","timestamp":1783678685234,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,7]]},"group-title":"Immunology","reference-count":18,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Advanced BRAF-mutant cutaneous melanoma can be treated with targeted therapy when immune checkpoint inhibitors (ICIs) fail or are not a feasible option. Nevertheless, most patients do not achieve a durable response, highlighting the critical need for therapeutic partners that enhance the long-term efficacy of targeted therapy. Transcriptomic analysis of a BRAF-mutant melanoma model of acquired resistance identified P-selectin glycoprotein ligand-1 (PSGL-1) as a top-upregulated immune mediator upon resistance acquisition. PSGL-1 is a key regulator of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell exhaustion and differentiation, and its inhibition has been shown to enhance T cell function across multiple disease models. Based on these observations, we hypothesized that combined targeting of BRAF\/MEK and PSGL-1 would improve anti-tumor responses.\n                <\/jats:p>\n                <jats:p>\n                  Here, we demonstrate that dual inhibition of BRAF\/MEK and PSGL-1 elicits durable tumor control in a preclinical model of PD-1-refractory cutaneous melanoma. Single-cell RNA sequencing of the tumor microenvironment reveals robust reprogramming of intratumoral CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells toward a less terminally differentiated, memory-like phenotype following combined BRAF\/MEK and PSGL-1 targeting. Consistent with these findings, CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the tumor-draining lymph nodes of PSGL-1\n                  <jats:sup>-\/-<\/jats:sup>\n                  mice exhibit enhanced functionality and a less differentiated state of exhaustion when compared with wild-type mice. To extend these observations to a translationally relevant setting, we further show that antibody-mediated blockade of PSGL-1, in combination with BRAF\/MEK inhibition, yields superior anti-tumor activity compared with either monotherapy. Collectively, these findings identify PSGL-1 as a promising therapeutic target to enhance the durability of targeted therapy and provide a strong rationale for future clinical evaluation.\n                <\/jats:p>","DOI":"10.64898\/2026.07.02.736105","type":"posted-content","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:50:16Z","timestamp":1783489816000},"source":"Crossref","is-referenced-by-count":0,"title":["PSGL-1 blockade delays relapse to BRAF\/MEK inhibition in cutaneous melanoma"],"prefix":"10.64898","author":[{"given":"OS","family":"El Naggar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BN","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ML","family":"Rakoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Cort","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Amirfallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EA","family":"Haglund","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Urquiza","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HAF","family":"Hetrick","sequence":"additional","affiliation":[{"name":"Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LM","family":"Bradley","sequence":"additional","affiliation":[{"name":"Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EJ","family":"Hartsough","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"},{"name":"Translational and Cellular Oncology Program, NCI-Designated Comprehensive Cancer Center, Sidney Kimmel Comprehensive Cancer Center, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JL","family":"Hope","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102"},{"name":"Immune Cell Regulation & Targeting Program, NCI-Designated Comprehensive Cancer Center, Sidney Kimmel Comprehensive Cancer Center, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102"},{"name":"Immune Cell Regulation & Targeting Program, NCI-Designated Comprehensive Cancer Center, Sidney Kimmel Comprehensive 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