{"id":21625,"date":"2025-01-09T06:47:54","date_gmt":"2025-01-09T05:47:54","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/01\/09\/trabectedin-enhances-the-antitumor-effects-of-il-12-in-triple-negative-breast-cancer\/"},"modified":"2025-01-09T06:47:54","modified_gmt":"2025-01-09T05:47:54","slug":"trabectedin-enhances-the-antitumor-effects-of-il-12-in-triple-negative-breast-cancer","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/01\/09\/trabectedin-enhances-the-antitumor-effects-of-il-12-in-triple-negative-breast-cancer\/","title":{"rendered":"Trabectedin enhances the antitumor effects of IL-12 in triple-negative breast cancer"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Jan 7. doi: 10.1158\/2326-6066.CIR-24-0775. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Interleukin-12 (IL-12) is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 in triple-negative breast cancer (TNBC). In vitro treatment of healthy donor NK cells with trabectedin increased expression of the activation marker CD69 and mRNA expression of T BET (Tbx21), the cytotoxic ligands TRAIL (TNFSF10) and Fas ligand (FASLG) and the dendritic cell (DC)-recruiting chemokine lymphotactin (XCL1). The combination of IL-12 and trabectedin increased NK-cell cytotoxicity, activation and production of IFN-\u03b3, TNF-\u03b1 and granzyme B in the presence of human TNBC cells. Treatment of 4T1 and EMT6 tumor-bearing mice with IL-12 and trabectedin led to a significant reduction in tumor burden compared to single-agent controls, and the highest levels of plasma IFN-\u03b3, intratumoral CD8+ T cells and conventional type 1 DC. MDSC and M2-like macrophages were significantly decreased with combination therapy. NK-cell depletion abrogated the effects of combination therapy, as did elimination of CD8+ T cells. NK-cell depletion led to lower levels of the NK cell-derived chemokine CCL5 and the DC-derived chemokine CXCL10, higher tumor burden, and decreased intratumoral CD8+ T cells. IL 12 and trabectedin also significantly enhanced the response of TNBC to anti-PD-L1 therapy. These data suggest that MDSC depletion augments the ability of IL-12-activated NK cells to drive the infiltration of DC and CD8+ T cells into TNBC for an antitumor effect.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39777457\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250109004753&amp;v=2.18.0.post9+e462414\">39777457<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0775\">10.1158\/2326-6066.CIR-24-0775<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Jan 7. doi: 10.1158\/2326-6066.CIR-24-0775. Online ahead of print. ABSTRACT Interleukin-12 (IL-12) is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 &#8230; <a title=\"Trabectedin enhances the antitumor effects of IL-12 in triple-negative breast cancer\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/01\/09\/trabectedin-enhances-the-antitumor-effects-of-il-12-in-triple-negative-breast-cancer\/\" aria-label=\"Read more about Trabectedin enhances the antitumor effects of IL-12 in triple-negative breast 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-21625","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\/21625","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=21625"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/21625\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=21625"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=21625"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=21625"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}