Synergistic action of gemcitabine and celecoxib in promoting the antitumor efficacy of anti-programmed death-1 monoclonal antibody by triggering immunogenic cell death

Article

作者: Zhang, Wenkai ; Zhu, Xiongjie ; Yang, Xia ; Yu, Zhongjian ; Djumanazarov, Temirbek ; Piquemal, David ; Zheng, Yanfang ; Chen, Cuicui ; Yusupbekov, Abrorjon A ; Li, Laiqing

BackgroundEmerging evidence suggests that immunogenic chemotherapy not only kills tumor cells but also improves the immune-suppressive tumor microenvironment by inducing immunogenic cell death (ICD), leading to sustained anti-tumor effects. The lack of ICD inducers explored in lung cancer necessitates investigation into new inducers for this context, therefore, this study aims to explore whether the gemcitabine (GEM) and celecoxib can activate the immunogenic chemotherapy progress in lung cancer tissue.MethodsWe assessed five chemotherapeutic agents for their ability to trigger ICD using ex vivo and in vivo experiments, including western blotting (WB), flow cytometry, and tumor preventive vaccine assays. Additionally, we evaluated the synergistic effects of GEM, celecoxib, and anti-programmed death 1 monoclonal antibody (aPD-1) in tumor-bearing mice to understand how GEM activates antitumor immunity and enhances immunochemotherapy.ResultsGEM was identified as an effective ICD inducer, showing high expression of calreticulin (CRT) and heat shock protein 90 (HSP90). Co-culture with GEM-treated cells [Lewis lung carcinoma (LLC) and CMT-64] enhanced dendritic cell (DC) activity, evidenced by maturation markers and increased phagocytic capacity. Moreover, celecoxib was found to enhance ICD by reducing indoleamine 2,3-dioxygenase 1 (IDO1) expression and increasing reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress. The combination therapy [GEM, celecoxib, and aPD-1 (GCP)] exhibited potent and sustained antitumor activity in immunocompetent mice, with enhanced recruitment of tumor-infiltrating lymphocytes.ConclusionsThese findings support the potential use of GCP therapy as a treatment option for lung cancer patients.

2024-04-03·Cureus

Diffuse Interstitial Lung Disease Revealing Antisynthetase Syndrome

作者: Haouassia, Fatima Ezzahra ; Benjelloun, Hanane ; Chaanoune, Khadija ; Yassine, Najiba ; Zaghba, Nahid

Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases. They may be revelatory of the disease or occur during follow-up. Antisynthetase syndrome (ASS) is a complex and heterogeneous autoimmune disorder. Antisynthetase antibodies, in particular the anti-Jo-1 antibody, characterize this syndrome. The occurrence and severity of ILD determine the prognosis, which in turn determines therapeutic management. We report the case of a 53-year-old female patient presenting with ILD, revealing the diagnosis of ASS. The evolution was favorable with bolus corticosteroids associated with cyclophosphamide.

2023-12-18·Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences

[Significance of anti-Jo-1 antibody's clinical stratification in idiopathic inflammatory myopathy and disease spectrum].

Article

作者: Li, Yu Hui ; Zhang, Yan Ying ; Li, Zhan Guo ; Gao, Xiao Juan ; Lai, Zhan Hong ; Zhang, Ke ; Li, Jia Chen ; Jin, Yue Bo ; Hou, Jing ; Shao, Miao

OBJECTIVETo investigate the significance of anti-histidyl tRNA synthetase (Jo-1) antibody in idiopathic inflammatory myopathies (IIM) and its diseases spectrum.METHODSWe enrolled all the patients who were tested positive for anti-Jo-1 antibody by immunoblotting in Peking University People's Hospital between 2016 and 2022. And the patients diagnosed with anti-synthetase antibody syndrome (ASS) with negative serum anti-Jo-1 antibody were enrolled as controls. We analyzed the basic information, clinical characteristics, and various inflammatory and immunological indicators of the patients at the onset of illness.RESULTSA total of 165 patients with positive anti-Jo-1 antibody were enrolled in this study. Among them, 80.5% were diagnosed with connective tissue disease. And 57.6% (95/165) were diagnosed with IIM, including ASS (84/165, 50.9%), immune-mediated necrotizing myopathy (7/165, 4.2%) and dermatomyositis (4/165, 2.4%). There were 23.0% (38/165) diagnosed with other connective tissue disease, mainly including rheumatoid arthritis (11/165, 6.7%), undifferentiated connective tissue disease (5/165, 3.0%), interstitial pneumonia with autoimmune features (5/165, 3.0%), undifferentiated arthritis (4/165, 2.4%), Sjögren's syndrome (3/165, 1.8%), systemic lupus erythematosus (3/165, 1.8%), systemic vasculitis (3/165, 1.8%), and so on. Other cases included 3 (1.8%) malignant tumor patients, 4 (2.4%) infectious cases and so on. The diagnoses were not clear in 9.1% (15 /165) of the cohort. In the analysis of ASS subgroups, the group with positive serum anti-Jo-1 antibody had a younger age of onset than those with negative serum anti-Jo-1 antibody (49.9 years vs. 55.0 years, P=0.026). Clinical manifestations of arthritis (60.7% vs. 33.3%, P=0.002) and myalgia (47.1% vs. 22.2%, P=0.004) were more common in the ASS patients with positive anti-Jo-1 antibody. With the increase of anti-Jo-1 antibody titer, the incidence of the manifestations of arthritis, mechanic hands, Gottron sign and Raynaud phenomenon increased, and the proportion of abnormal creatine kinase and α-hydroxybutyric dehydrogenase index increased in the ASS patients. The incidence of myalgia and myasthenia were significantly more common in this cohort when anti-Jo-1 antibody-positive ASS patients were positive for one and more myositis specific antibodies/myositis associated autoantibodies (P < 0.05).CONCLUSIONThe disease spectrum in patients with positive serum anti-Jo-1 antibody includes a variety of diseases, mainly ASS. And anti-Jo-1 antibody can also be found in many connective tissue diseases, malignant tumor, infection and so on.

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适应症	国家/地区	公司	日期
移植物抗宿主病	法国	-	1997-01-01
肾移植排斥反应	法国	-	1997-01-01

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移植物功能延迟恢复	临床2期	美国	Immunotech	-
移植物功能延迟恢复	临床2期	欧盟	Immunotech	-
移植物功能延迟恢复	临床2期	加拿大	Immunotech	-