Combined inhibition of PD-1/PD-L1, Lag-3, and Tim-3 axes augments antitumor immunity in gastric cancer–T cell coculture models
| العنوان: | Combined inhibition of PD-1/PD-L1, Lag-3, and Tim-3 axes augments antitumor immunity in gastric cancer–T cell coculture models |
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| المؤلفون: | Zul Fazreen, Kosaku Mimura, Nicholas Syn, Yuko Nakayama, Jin-Fen Xiao, Wei Peng Yong, Richie Soong, Koji Kono, Bernadette Reyna Asuncion, Ley-Fang Kua |
| المصدر: | Gastric Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, Tim-3, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigens, CD, Stomach Neoplasms, Cell Line, Tumor, PD-L1, PD-1, Humans, Medicine, Cytotoxic T cell, Lectins, C-Type, Cytotoxicity, Aged, Singapore, MHC class II, biology, business.industry, Lag-3, Gastroenterology, General Medicine, Immunotherapy, Survival Analysis, Gene Expression Regulation, Neoplastic, CTL, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Original Article, Combinatorial immunotherapy, Female, Gastric cancer, business, Cell Adhesion Molecules |
| الوصف: | Background Immunotherapy targeting PD-1 provides a limited survival benefit in patients with unresectable advanced or recurrent gastric cancer (GC). Beside PD-L1, the expression of inhibitory ligands such as CEACAM-1 and LSECtin on GC cells account for this limitation. Here we assessed their expression and immune suppressive effect in GC patients. Methods Using multiplexed immunohistochemistry staining, we evaluated the distribution of different inhibitory ligands, including PD-L1, CEACAM-1, LSECtin, and MHC class II, in 365 GC patients. We analyzed their correlations and overall survival (OS) based on the expression of each inhibitory ligand and the independent prognostic factors that affect OS. Subsequently, we evaluated the additive effect of anti-PD-1 mAb or anti-PD-L1 mAb with/without anti-Lag-3 mAb with/without anti-Tim-3 mAb in cytotoxic assay using tumor-antigen specific CTL clones against GC cell lines. Results Co-expression of the inhibitory ligands for PD-1, Tim-3, and Lag-3 was observed in the largest proportion (34.7%). CEACAM-1, LSECtin, and MHC class II expression showed significant correlation with PD-L1 expression and OS. Multivariable analysis demonstrated that CEACAM-1 low is an independent prognostic factor. Furthermore, combining dual and triple ICIs yielded additive effect on cytotoxicity of CTL clones against each immune inhibitory ligand positive GC cell lines. Conclusions Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients. |
| تدمد: | 1436-3305 1436-3291 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b04fb8da0f849665868f13e779a7156Test https://doi.org/10.1007/s10120-020-01151-8Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7b04fb8da0f849665868f13e779a7156 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14363305 14363291 |
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