{"id":24239,"date":"2025-02-11T18:53:47","date_gmt":"2025-02-11T17:53:47","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/02\/11\/tlr5-signaling-causes-dendritic-cell-dysfunction-and-orchestrates-failure-of-immune-checkpoint-therapy-against-ovarian-cancer\/"},"modified":"2025-02-11T18:53:47","modified_gmt":"2025-02-11T17:53:47","slug":"tlr5-signaling-causes-dendritic-cell-dysfunction-and-orchestrates-failure-of-immune-checkpoint-therapy-against-ovarian-cancer","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/02\/11\/tlr5-signaling-causes-dendritic-cell-dysfunction-and-orchestrates-failure-of-immune-checkpoint-therapy-against-ovarian-cancer\/","title":{"rendered":"TLR5 signaling causes dendritic-cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Feb 11. doi: 10.1158\/2326-6066.CIR-24-0513. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients who have ovarian tumors infiltrated with high frequencies of T cells are associated with a greater survival probability. However, therapies to revitalize tumor-associated T cells, such as PD-L1\/PD-1 or CTLA4 blockade, are ineffective for the treatment of ovarian cancer. In this study, we demonstrate that for ovarian cancer, Toll-Like Receptor 5 (TLR5) signaling, for which the only known ligand is bacterial flagellin, governed failure of PD-L1 and CTLA4 blockade. Mechanistically, chronic TLR5 signaling on CD11c+ cells in vivo and in vitro impaired the differentiation of functional IL-12-producing XCR1+CD103+ conventional type 1 dendritic cells (cDC1), biasing CD11c+ precursor cells toward myeloid subsets expressing high levels of PD-L1. This culminated in impaired activation of CD8+ T cells, reducing CD8+ T-cell function and ability to persist within the ovarian tumor microenvironment. Expansion of cDC1s in situ using FLT3L in combination with PD-L1 blockade achieved significant survival benefit in TLR5 knockout mice bearing ovarian tumors, whereas no benefit was observed in the presence of TLR5 signaling. Thus, we have identified a host-intrinsic mechanism leading to the failure of PD-L1 blockade for ovarian cancer, demonstrating that chronic TLR5 signaling on CD11c+ cells is a barrier limiting the efficacy of checkpoint therapy.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39932226\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250211125347&amp;v=2.18.0.post9+e462414\">39932226<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0513\">10.1158\/2326-6066.CIR-24-0513<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Feb 11. doi: 10.1158\/2326-6066.CIR-24-0513. Online ahead of print. ABSTRACT Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients who have ovarian tumors infiltrated with high frequencies of T cells are associated with a greater survival probability. However, therapies to revitalize tumor-associated T cells, such &#8230; <a title=\"TLR5 signaling causes dendritic-cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/02\/11\/tlr5-signaling-causes-dendritic-cell-dysfunction-and-orchestrates-failure-of-immune-checkpoint-therapy-against-ovarian-cancer\/\" aria-label=\"Read more about TLR5 signaling causes dendritic-cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer\">Read more<\/a><\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-24239","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/24239","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=24239"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/24239\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=24239"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=24239"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=24239"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}