| 项目编号 |
PRJCA023207 |
| 项目标题 |
PARP inhibitors enhance anti-tumor immune responses by triggering pyroptosis via TNF-caspase8-GSDMD/E axis |
| 涉及领域 |
Medical |
| 数据类型 |
Transcriptome or Gene expression
Raw sequence reads
|
| 物种名称 |
Mus musculus
Homo sapiens
|
| 描述信息 |
Besides the well-established synthetic lethality, PARP inhibition can also trigger immune responses that contribute to tumor suppression. Yet the pharmacological effect remains incompletely understood. Using TCR-sequencing and histological analyses of mouse ID8 tumors and clinical specimens from a prospective study (NCT04507841), we found that PARP inhibitors triggered tumor immunogenic cell death (ICD), which resulted in the transition into a "hot" tumor immune microenvironment (TIME) and enhanced tumor-targeting immune responses. The ICD induced by PARP inhibitors has characteristics of pyroptosis such as classic morphological changes and GSDMD/E cleavage. This GSDMD/E cleavage was closely associated with the increased caspase 8 activity that was located downstream of the TNF signaling pathway but not FAS/FASL and TRAIL. PARP inhibition-activated NF-κB contributed to the secretion of TNF-α, resulting in the activation of caspase 8 without inhibition by c-FLIP. Blocking pyroptosis with the depletion of GSDMD and GSDME facilitated tumor growth and impaired immune response in a syngeneic mouse model. Hence, our data revealed a novel mechanism by which PARP inhibitors inflame TIME and drive tumor-targeting immune response, with potential applications in developing effective combinational therapies for tumors. |
| 样品范围 |
Multispecies |
| 发布日期 |
2024-10-26 |
| 出版信息 |
| PubMed ID |
文章标题 |
杂志名称 |
Doi |
发表年份 |
| 39366751
|
PARP inhibitors enhance antitumor immune responses by triggering pyroptosis via TNF–caspase 8–GSDMD/E axis in ovarian cancer
|
Journal for Immunotherapy of Cancer
|
10.1136/jitc-2024-009032
|
2024
|
|
|
| 项目资金来源 |
| 机构 |
项目类型 |
授权项目ID |
授权项目名称 |
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
National Key Technologies R&D Program
|
2022YFC2704200
|
|
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
National Key Technologies R&D Program
|
2022YFC2704205
|
|
| National Natural Science Foundation of China (NSFC)
|
|
81902933
|
|
| National Natural Science Foundation of China (NSFC)
|
|
82372928
|
|
| National Natural Science Foundation of China (NSFC)
|
|
82072889
|
|
|
|
| 提交者 |
Qinglei
Gao (qingleigao@hotmail.com)
|
| 提交单位 |
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology |
| 提交日期 |
2024-01-25 |
