LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer
Background Loss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009444.full |
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| author | Wei Liu Dong Wang Qing Miao Peilin Chen Hongbing Liu Jiawen Lv Jie Yin Jian Feng Yong Song Tangfeng Lv Mingxiang Ye Wenjie Yan Liting Lv Sutong Zhan |
| author_facet | Wei Liu Dong Wang Qing Miao Peilin Chen Hongbing Liu Jiawen Lv Jie Yin Jian Feng Yong Song Tangfeng Lv Mingxiang Ye Wenjie Yan Liting Lv Sutong Zhan |
| author_sort | Wei Liu |
| collection | DOAJ |
| description | Background Loss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy.Methods We investigated the mutational landscape of LKB1 mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling of LKB1 wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay.Results By using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched “hot” TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded “cold” TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling.Conclusion LKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from “hot” TME to “cold” TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy. |
| format | Article |
| id | doaj-art-a0fa5bc2c96a45fba7687772bd90de3b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a0fa5bc2c96a45fba7687772bd90de3b2024-12-18T15:00:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009444LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancerWei Liu0Dong Wang1Qing Miao2Peilin Chen3Hongbing Liu4Jiawen Lv5Jie Yin6Jian Feng7Yong Song8Tangfeng Lv9Mingxiang Ye10Wenjie Yan11Liting Lv12Sutong Zhan13Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China2 Cardiomyopathy Ward, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China2 The Saban Research Institute, Children`s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA1 Centre for Orthopaedic Research, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, AustraliaDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China1 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, ChinaSchool of Economics and Management, Shanghai Maritime University, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China1 Lab for Post-traumatic Stress Disorder, Faculty of Psychology, Naval Medical University, Shanghai, People`s Republic of ChinaDepartment of Respiratory Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, ChinaBackground Loss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy.Methods We investigated the mutational landscape of LKB1 mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling of LKB1 wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay.Results By using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched “hot” TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded “cold” TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling.Conclusion LKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from “hot” TME to “cold” TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy.https://jitc.bmj.com/content/12/12/e009444.full |
| spellingShingle | Wei Liu Dong Wang Qing Miao Peilin Chen Hongbing Liu Jiawen Lv Jie Yin Jian Feng Yong Song Tangfeng Lv Mingxiang Ye Wenjie Yan Liting Lv Sutong Zhan LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer Journal for ImmunoTherapy of Cancer |
| title | LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer |
| title_full | LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer |
| title_fullStr | LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer |
| title_full_unstemmed | LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer |
| title_short | LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer |
| title_sort | lkb1 dictates sensitivity to immunotherapy through skp2 mediated ubiquitination of pd l1 protein in non small cell lung cancer |
| url | https://jitc.bmj.com/content/12/12/e009444.full |
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