{"id":21706,"date":"2025-01-10T00:15:51","date_gmt":"2025-01-09T23:15:51","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/01\/10\/tbk1-targeting-is-identified-as-a-therapeutic-strategy-to-enhance-car-t-cell-efficacy-using-patient-derived-organotypic-tumor-spheroids\/"},"modified":"2025-01-10T00:15:51","modified_gmt":"2025-01-09T23:15:51","slug":"tbk1-targeting-is-identified-as-a-therapeutic-strategy-to-enhance-car-t-cell-efficacy-using-patient-derived-organotypic-tumor-spheroids","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/01\/10\/tbk1-targeting-is-identified-as-a-therapeutic-strategy-to-enhance-car-t-cell-efficacy-using-patient-derived-organotypic-tumor-spheroids\/","title":{"rendered":"TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Jan 9:OF1-OF19. doi: 10.1158\/2326-6066.CIR-23-1011. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and then confirmed the activity of B7-H3.CAR T cells in PDOTS. Although B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR T-cells following target cell encounter that led to CAR T-cell dysfunction and limited efficacy against B7-H3-expressing tumors. PD-1 blockade restored CAR T-cell activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR T-cell efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR T-cell activity in monotypic and organotypic tumor spheroids, prevented CAR T-cell dysfunction, and enhanced CAR T-cell proliferation. Inhibition or deletion of TBK1 also enhanced the sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR T cells using PDOTS and suggest that targeting TBK1 could be used to enhance CAR T-cell efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39785827\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250109181550&amp;v=2.18.0.post9+e462414\">39785827<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-23-1011\">10.1158\/2326-6066.CIR-23-1011<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Jan 9:OF1-OF19. doi: 10.1158\/2326-6066.CIR-23-1011. Online ahead of print. ABSTRACT Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model &#8230; <a title=\"TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/01\/10\/tbk1-targeting-is-identified-as-a-therapeutic-strategy-to-enhance-car-t-cell-efficacy-using-patient-derived-organotypic-tumor-spheroids\/\" aria-label=\"Read more about TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids\">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-21706","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\/21706","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=21706"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/21706\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=21706"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=21706"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=21706"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}