{"id":42360,"date":"2025-09-08T18:49:18","date_gmt":"2025-09-08T16:49:18","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/09\/08\/non-redundant-immune-checkpoints-direct-therapeutic-resistance-to-chemoimmunotherapy-in-pancreatic-ductal-adenocarcinoma\/"},"modified":"2025-09-08T18:49:18","modified_gmt":"2025-09-08T16:49:18","slug":"non-redundant-immune-checkpoints-direct-therapeutic-resistance-to-chemoimmunotherapy-in-pancreatic-ductal-adenocarcinoma","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/09\/08\/non-redundant-immune-checkpoints-direct-therapeutic-resistance-to-chemoimmunotherapy-in-pancreatic-ductal-adenocarcinoma\/","title":{"rendered":"Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Sep 8. doi: 10.1158\/2326-6066.CIR-25-0575. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Pancreatic ductal adenocarcinoma (PDA) is defined by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., PD-1 and CTLA-4). Here, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that depletion of CSF1R+ myeloid cells in combination with anti-PD-1 and chemotherapy triggers T cell infiltration into PDA but causes compensatory remodeling of the myeloid compartment with limited tumor control. Unexpectedly, combined therapy against multiple myeloid targets including CSF1R, CCR2\/5 and CXCR2 was insufficient to overcome treatment resistance. High-dimensional single cell analyses performed on T cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40920092\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250908124914&amp;v=2.18.0.post9+e462414\">40920092<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-25-0575\">10.1158\/2326-6066.CIR-25-0575<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Sep 8. doi: 10.1158\/2326-6066.CIR-25-0575. Online ahead of print. ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is defined by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., PD-1 and CTLA-4). Here, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that depletion &#8230; <a title=\"Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/09\/08\/non-redundant-immune-checkpoints-direct-therapeutic-resistance-to-chemoimmunotherapy-in-pancreatic-ductal-adenocarcinoma\/\" aria-label=\"Read more about Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-42360","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\/42360","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"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=42360"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/42360\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=42360"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=42360"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=42360"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}