{"id":10415,"date":"2026-07-16T06:00:00","date_gmt":"2026-07-16T13:00:00","guid":{"rendered":"https:\/\/keck.usc.edu\/news\/?p=10415"},"modified":"2026-07-21T11:22:10","modified_gmt":"2026-07-21T18:22:10","slug":"study-reveals-why-some-colorectal-cancers-respond-better-to-immunotherapy","status":"publish","type":"post","link":"https:\/\/keck.usc.edu\/news\/study-reveals-why-some-colorectal-cancers-respond-better-to-immunotherapy\/","title":{"rendered":"Study reveals why some colorectal cancers respond better to immunotherapy"},"content":{"rendered":"\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--article-hero \"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--article-hero\"\n    \n      >\n\n    \n  <div class=\"text-container\">\n              \n<div class=\"f--field f--eyebrow\">\n\n    \n  <span>Press Release<\/span>\n\n\n\n<\/div>\n    \n              \n<div class=\"f--field f--page-title\">\n\n    \n      <h1>Study reveals why some colorectal cancers respond better to immunotherapy<\/h1>\n\n\n<\/div>\n    \n              \n<div class=\"f--field f--description\">\n\n    \n  <p>Using animal models and patient tumor data, researchers from the Keck School of Medicine of USC identified a biological pathway that helps activate the immune response against certain types of cancer.<\/p>\n\n\n\n<\/div>\n    \n          <div class=\"meta\">\n                  <span class=\"author\">Zara Abrams<\/span>\n        \n                  <span class=\"date\">July 16, 2026<\/span>\n              <\/div>\n    \n              \n<div class=\"f--field f--embed\">\n\n    \n  <div class=\"heateor_sss_sharing_container heateor_sss_horizontal_sharing\" data-heateor-ss-offset=\"0\" data-heateor-sss-href='https:\/\/keck.usc.edu\/news\/study-reveals-why-some-colorectal-cancers-respond-better-to-immunotherapy\/'><div class=\"heateor_sss_sharing_ul\"><a aria-label=\"Facebook\" class=\"heateor_sss_facebook\" 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.26.015.37.046.114.03.23.09.346.175.117.085.202.153.256.2.054.05.15.148.29.29.14.146.222.23.25.258.294-.278.442-.606.442-.983zM27 21.177c0 1.078-.382 1.99-1.146 2.736l-1.982 1.968c-.745.75-1.658 1.12-2.736 1.12-1.087 0-2.004-.38-2.75-1.143l-2.777-2.79c-.75-.747-1.12-1.66-1.12-2.737 0-1.106.392-2.046 1.183-2.818l-1.186-1.185c-.774.79-1.708 1.186-2.805 1.186-1.078 0-1.995-.376-2.75-1.13l-2.803-2.81C5.377 12.82 5 11.903 5 10.826c0-1.08.382-1.993 1.146-2.738L8.128 6.12C8.873 5.372 9.785 5 10.864 5c1.087 0 2.004.382 2.75 1.146l2.777 2.79c.75.747 1.12 1.66 1.12 2.737 0 1.105-.392 2.045-1.183 2.817l1.186 1.186c.774-.79 1.708-1.186 2.805-1.186 1.078 0 1.995.377 2.75 1.132l2.804 2.804c.754.755 1.13 1.672 1.13 2.75z\"\/><\/svg><\/span><\/a><\/div><div class=\"heateorSssClear\"><\/div><\/div>\n\n\n<\/div>\n        \n  <\/div>\n\n          \n<div class=\"f--field f--image\">\n\n    \n    \n    \n        <figure>\n    \n    \n    \n              \n      <img\n                            data-src=\"https:\/\/keck.usc.edu\/news\/wp-content\/uploads\/sites\/68\/2026\/07\/iStock-2196576063-768x432.jpg\"\n          data-srcset=\"https:\/\/keck.usc.edu\/news\/wp-content\/uploads\/sites\/68\/2026\/07\/iStock-2196576063-1920x1080.jpg 1920w,https:\/\/keck.usc.edu\/news\/wp-content\/uploads\/sites\/68\/2026\/07\/iStock-2196576063-1280x720.jpg 1280w,https:\/\/keck.usc.edu\/news\/wp-content\/uploads\/sites\/68\/2026\/07\/iStock-2196576063-768x432.jpg 768w\"          data-sizes=\"(min-width:1200px) 75vw, (min-width:768px) 83vw, 100vw\"          class=\"lazyload\"\n        \n                alt=\"A cancer cell is being targeted by immune cells\"\n\n        \n                \n                                      \/>\n\n    \n          <figcaption><p>Photo\/iStock<\/p>\n<\/figcaption>\n    <\/figure>\n    \n  \n  \n\n<\/div>\n  \n\n  <\/div><\/div>\n\n\n\n\n  \n    \n\n\n\n\n\n\n<div\n  class=\"cc--component-container cc--rich-text white\"\n\n  \n  \n  \n  \n  \n  \n  >\n  <div class=\"c--component c--rich-text\"\n    \n      >\n\n    \n  <div class=\"inner-wrapper\">\n        \n<div class=\"f--field f--wysiwyg\">\n\n    \n  <p><span style=\"font-weight: 400\">A subset of cancers, known as microsatellite instability (MSI) and deficient DNA mismatch repair (dMMR) cancers, are more visible to the immune system than others. Because their DNA repair systems are defective, these tumors are more likely to be recognized and attacked by immune cells and tend to respond better to immunotherapy. But scientists do not fully understand why.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Now, the answer is coming into focus. Researchers from the <\/span><a href=\"https:\/\/keck.usc.edu\/\"><span style=\"font-weight: 400\">Keck School of Medicine of USC<\/span><\/a><span style=\"font-weight: 400\"> discovered a biological feedback loop that helps the immune system recognize and attack colorectal cancers with MSI or dMMR. In mice, they found that two genes\u2014Death Receptor 5 (DR5) and Ligase 3 (Lig3)\u2014help drive a cycle of tumor cell death and immune system activation. They also found that human tumors with higher DR5 and Lig3 activity were more likely to respond to immune checkpoint inhibitors, a type of cancer immunotherapy.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The study, funded in part by the National Institutes of Health and just published in the journal Gastroenterology, may suggest a way to make immunotherapy more effective against cancers that respond poorly to treatment.<\/span><\/p>\n<p><span style=\"font-weight: 400\">\u201cWe\u2019ve gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle,\u201d said lead author <\/span><a href=\"https:\/\/keck.usc.edu\/faculty-search\/lin-zhang\/\"><span style=\"font-weight: 400\">Lin Zhang, PhD<\/span><\/a><span style=\"font-weight: 400\">, professor of medicine and the Mark A., J. Ruth and Stillman F. Sawyer Chair of Oncology at the Keck School of Medicine. \u201cOur hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment.\u201d<\/span><\/p>\n<p><b>A positive feedback loop<\/b><\/p>\n<p><span style=\"font-weight: 400\">To investigate what makes MSI and dMMR cancers different, Zhang and his colleagues created a mouse model of the disease by disabling a key DNA repair gene in tumor cells. They then implanted the altered cells into healthy mice to watch the immune response unfold.<\/span><\/p>\n<p><span style=\"font-weight: 400\">As the mice mounted an immune response to the tumors, the researchers tracked changes in cell signaling, cell behavior and gene activity. Two genes\u2014DR5 and Lig3\u2014emerged as key players.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The DNA repair defect caused the tumor cells to increase activity of the DR5 gene, triggering their own destruction. As the cells died, they released extrachromosomal circular DNA (eccDNA), small circular pieces of DNA that are separate from the cell\u2019s main genetic material. More eccDNA was released when the Lig3 gene was highly active. The eccDNA, in turn, activated a broader immune response, creating a positive feedback loop that helped the immune system mount an ongoing attack against the tumor.<\/span><\/p>\n<p><span style=\"font-weight: 400\">To validate their findings, the researchers then analyzed data from human patients. Looking at gene expression in colorectal cancers, they found that tumors with higher levels of DR5 and Lig3 activity responded better to treatment with immune checkpoint inhibitors.<\/span><\/p>\n<p><span style=\"font-weight: 400\">\u201cOne of the most encouraging parts of the study was seeing that the same signals showed up in patient tumors,\u201d Zhang said. \u201cThat suggests we\u2019re uncovering a mechanism that could be clinically relevant.\u201d<\/span><\/p>\n<p><b>Boosting the immune response<\/b><\/p>\n<p><span style=\"font-weight: 400\">Looking ahead, the researchers aim to explore whether drugs that activate the DR5 pathway or increase eccDNA release could make immunotherapy more effective. They also plan to investigate whether DR5 and Lig3 could help personalize treatment choices by predicting who is most likely to benefit from immunotherapy.<\/span><\/p>\n<p><span style=\"font-weight: 400\">More research is needed before these approaches can be tested in patients, including studies of human colorectal tumor cells. Zhang will continue to work with <\/span><a href=\"https:\/\/keck.usc.edu\/faculty-search\/heinz-josef-lenz\"><span style=\"font-weight: 400\">Heinz-Josef Lenz, MD<\/span><\/a><span style=\"font-weight: 400\">, associate director for clinical research and co-leader of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center. Lenz, a coauthor of the study, contributed clinical expertise and access to patient datasets that allowed the team to compare their laboratory findings with real-world outcomes.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The findings may also have implications for other MSI and dMMR cancers, including some ovarian and endometrial cancers, which Zhang and his team hope to explore.<\/span><\/p>\n<p><b>About this research<\/b><\/p>\n<p><span style=\"font-weight: 400\">In addition to Zhang and Lenz, the study\u2019s other authors are Suisui Hao, Yoshiaki Sato, Francesca Battaglin, Karam Ashouri. Zhaojin Liu, Xinyan Lu and Jian Yu from the Department of Medicine and the USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California; Yi-Jun Wang, Darleny Lizardo and Robert E. Schoen from the Hillman Cancer Center, University of Pittsburgh School of Medicine; and Joanne Xiu and Matthew Oberley from Caris Life Sciences, Phoenix, Arizona.<\/span><\/p>\n<p><span style=\"font-weight: 400\">This work was supported in by the National Institutes of Health [R01CA236271, R01CA247231, R01CA248112, R01CA215481, R01CA260900] and start-up funds from the Keck School of Medicine of USC. The work used shared resources supported in part by the National Cancer Institute [P30CA047904, P30CA014089].<\/span><\/p>\n\n\n\n<\/div>\n  <\/div>\n\n\n  <\/div><\/div>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":278,"featured_media":10417,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[6],"tags":[10,226,446,169,20,86],"class_list":["post-10415","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-press-release","tag-cancer","tag-department-of-medicine","tag-homepage","tag-latest","tag-research","tag-usc-norris-comprehensive-cancer-center"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v28.2 (Yoast SEO v28.2) - 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