{"id":37308,"date":"2025-07-09T00:48:19","date_gmt":"2025-07-08T22:48:19","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/07\/09\/eml4-alk-rearrangement-creates-a-distinctive-myeloid-cell-dominant-immunosuppressive-microenvironment-in-lung-cancer\/"},"modified":"2025-07-09T00:48:19","modified_gmt":"2025-07-08T22:48:19","slug":"eml4-alk-rearrangement-creates-a-distinctive-myeloid-cell-dominant-immunosuppressive-microenvironment-in-lung-cancer","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/07\/09\/eml4-alk-rearrangement-creates-a-distinctive-myeloid-cell-dominant-immunosuppressive-microenvironment-in-lung-cancer\/","title":{"rendered":"EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Jul 8. doi: 10.1158\/2326-6066.CIR-24-0532. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Tyrosine kinase inhibitors (TKIs) are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma (ALK+ LUAD), but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for TKI-resistant cases. Although the use of immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with lung cancer, patients with ALK+ LUAD exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. Here, we explored the immunological status of the tumor microenvironment (TME) in ALK+ LUAD tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSCs) relative to ALK- LUAD cases, indicating that ALK+ LUAD has a myeloid cell-dominant immunosuppressive TME. Single-cell RNA-sequencing analysis identified a subset of macrophages that expressed most T cell-attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ LUAD. In contrast, ALK+ LUAD expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ LUAD showed higher levels of IL-6, an MDSC-inducing cytokine, than ALK- LUAD. An IL-6R inhibitor transformed the TME in a murine ALK+ LUAD model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL-6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene-mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ LUAD.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40627846\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250708184817&amp;v=2.18.0.post9+e462414\">40627846<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0532\">10.1158\/2326-6066.CIR-24-0532<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Jul 8. doi: 10.1158\/2326-6066.CIR-24-0532. Online ahead of print. ABSTRACT Tyrosine kinase inhibitors (TKIs) are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma (ALK+ LUAD), but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for TKI-resistant cases. Although the use of immune checkpoint inhibitors (ICIs) has improved &#8230; <a title=\"EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/07\/09\/eml4-alk-rearrangement-creates-a-distinctive-myeloid-cell-dominant-immunosuppressive-microenvironment-in-lung-cancer\/\" aria-label=\"Read more about EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer\">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-37308","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\/37308","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=37308"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/37308\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=37308"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=37308"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=37308"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}