{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:27:22Z","timestamp":1787120842624,"version":"build-2736575974"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08CA252164"],"award-info":[{"award-number":["K08CA252164"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009075","name":"Bankhead-Coley Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009075","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      pAc\/Emm55 (IFx-Hu2.0) is a plasmid DNA therapy encoding a\n                      <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                      -derived bacterial gene. It shows anti-tumor activity in preclinical models, but the mechanisms of anti-melanoma immunity and additive effects with immune checkpoint blockade remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>B16 melanoma tumor-bearing mice were treated intratumorally with pAc\/Emm55 alone and\/or intraperitoneally with PD-1, CTLA-4, or LAG-3 blockade and monitored for tumor growth. Antibodies against Emm55 and melanoma cells (B16 or YUMM) were quantified by flow cytometry. Bone marrow-derived dendritic cells (BMDCs) from WT, MyD88 KO, TLR2 KO, or TLR7 KO mice were assessed for antigen uptake, OVA cross-presentation, and OT-I priming after pulsing with cell lysates from Emm55- or empty-transfected melanoma cells. Tumor immune infiltration by CD8 and CD11c cells were evaluated by immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IFx-Hu2.0 significantly reduced tumor growth, correlating with increased intratumoral CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration and enhanced systemic antibody responses against melanoma cells. TLR deficiency did not alter OVA uptake or basal BMDC cross-presentation. However, Emm55-enhanced OT-I priming and IFN-\u03b3 production required TLR2 and MyD88, but not TLR7, supporting a TLR2\u2013MyD88\u2013dependent mechanism. Emm55 monotherapy and anti\u2013PD-1 each reduced tumor burden. The combination further improved inhibition. Adding anti-CTLA-4 or anti-LAG-3 to anti\u2013PD-1 did not provide additional meaningful benefit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Emm55 facilitates the TLR2\u2013MyD88 pathway in DCs and subsequent IFN-\u03b3 production by OT-I CD8 T cells. Combining intratumoral IFx-Hu2.0 with PD-1 blockade improves tumor control, supporting clinical evaluation of this strategy as also suggested by the first-in-human clinical trial of IFx-Hu2.0.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1863894","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:45:07Z","timestamp":1787118307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["pAc\/Emm55 increases anti-melanoma immunity via TLR2 signaling in dendritic cells and improves checkpoint blockade efficacy"],"prefix":"10.3389","volume":"17","author":[{"given":"Thi Hong Nga","family":"Le","sequence":"first","affiliation":[{"name":"Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quang Tam","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngchul","family":"Kim","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, FL, United States"]},{"name":"The Immuno-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute","place":["Tampa, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishanna","family":"Balkaran","sequence":"additional","affiliation":[{"name":"Department of Cutaneous Oncology, H. 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