Reference - Detail
| RRC ID | 81263 |
|---|---|
| Author | Chiba M, Shimono J, Suto K, Ishio T, Endo T, Goto H, Hasegawa H, Maeda M, Teshima T, Yang Y, Nakagawa M. |
| Title | Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma. |
| Journal | 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. |
| Volume | 143(14) |
| Pages | 1379-1390 |
| Published | 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 7 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |