| RRC ID |
81263
|
| 著者 |
Chiba M, Shimono J, Suto K, Ishio T, Endo T, Goto H, Hasegawa H, Maeda M, Teshima T, Yang Y, Nakagawa M.
|
| タイトル |
Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma.
|
| ジャーナル |
Blood
|
| Abstract |
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells are still unknown. To comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression, whereas STAT3 positively did so. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it, respectively. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain patients with primary ATLL. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared with each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody avelumab and chimeric antigen receptor (CAR) T cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells.
|
| 巻・号 |
143(14)
|
| ページ |
1379-1390
|
| 公開日 |
2024-4-4
|
| DOI |
10.1182/blood.2023021423
|
| PII |
S0006-4971(23)14733-1
|
| PMID |
38142436
|
| PMC |
PMC11033594
|
| MeSH |
Adult
B7-H1 Antigen / metabolism
Clustered Regularly Interspaced Short Palindromic Repeats
Cyclopentanes*
Humans
Leukemia-Lymphoma, Adult T-Cell* / drug therapy
Leukemia-Lymphoma, Adult T-Cell* / genetics
Leukemia-Lymphoma, Adult T-Cell* / pathology
Lymphoma* / genetics
Pyrimidines*
|
| IF |
17.794
|
| リソース情報 |
| 遺伝子材料 |
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
