| Accession |
PRJCA023207 |
| Title |
PARP inhibitors enhance anti-tumor immune responses by triggering pyroptosis via TNF-caspase8-GSDMD/E axis |
| Relevance |
Medical |
| Data types |
Transcriptome or Gene expression
Raw sequence reads
|
| Organisms |
Mus musculus
Homo sapiens
|
| Description |
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. |
| Sample scope |
Multispecies |
| Release date |
2024-10-26 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
| 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
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| 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
|
|
|
|
| Submitter |
Qinglei
Gao (qingleigao@hotmail.com)
|
| Organization |
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology |
| Submission date |
2024-01-25 |
