{"id":19782,"date":"2024-11-28T03:05:12","date_gmt":"2024-11-28T02:05:12","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2024\/11\/28\/blocking-wnt7a-enhances-mhc-i-antigen-presentation-and-enhances-the-effectiveness-of-immune-checkpoint-blockade-therapy\/"},"modified":"2024-11-28T03:05:12","modified_gmt":"2024-11-28T02:05:12","slug":"blocking-wnt7a-enhances-mhc-i-antigen-presentation-and-enhances-the-effectiveness-of-immune-checkpoint-blockade-therapy","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2024\/11\/28\/blocking-wnt7a-enhances-mhc-i-antigen-presentation-and-enhances-the-effectiveness-of-immune-checkpoint-blockade-therapy\/","title":{"rendered":"Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy"},"content":{"rendered":"<div>\n<p>Cancer Immunol Res. 2024 Nov 27. doi: 10.1158\/2326-6066.CIR-24-0484. Online ahead of print.<\/p>\n<p>ABSTRACT<\/p>\n<p>The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated Wnt\/\u03b2-catenin signaling pathway and thus resulted in reduced physical interaction between \u03b2-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-\u03baB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39602462\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20241127210511&amp;v=2.18.0.post9+e462414\">39602462<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0484\">10.1158\/2326-6066.CIR-24-0484<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2024 Nov 27. doi: 10.1158\/2326-6066.CIR-24-0484. Online ahead of print. ABSTRACT The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between &#8230; <a title=\"Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2024\/11\/28\/blocking-wnt7a-enhances-mhc-i-antigen-presentation-and-enhances-the-effectiveness-of-immune-checkpoint-blockade-therapy\/\" aria-label=\"Read more about Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy\">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-19782","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\/19782","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=19782"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/19782\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=19782"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=19782"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=19782"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}