期刊
CELL REPORTS
卷 39, 期 7, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2022.110814
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资金
- NIH/NCI [R01 CA258784]
- Congressionally Directed Medical Research Programs (DOD-IITRA) [LC190161]
- Parker Institute for Cancer Immunotherapy grant
- LCFA-BMS/ILC Foundation Young Investigator Research Awards in Translational Immuno-oncology
- Druckenmiller Center for Lung Cancer Research
- Yasuda Medical Foundation
- NCI [R01 CA197936, U24 CA213274]
- NIH [K08 CA-248723]
- Geoffrey Beene Foundation
- Van Andel Institute - Stand Up to Cancer Epigenetics Dream Team grant
- American Association for Cancer Research, the Scientific Partner of SU2C
- NCI Cancer Center Support Grant (CCSG) [P30 CA008748]
- Cycle for Survival
- Marie-Jose'e and Henry R. Kravis Center for Molecular Oncology
Inhibition of WEE1 in small cell lung cancer models activates the STING-TBK1-IRF3 pathway and increases type I interferons and pro-inflammatory chemokines, promoting an immune response. WEE1 inhibition also activates the STAT1 pathway and increases IFN-gamma and PD-L1 expression. Combined inhibition of WEE1 and PD-L1 leads to tumor regression and infiltration of cytotoxic T cells, indicating a promising immunotherapeutic approach.
Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-alpha and IFN-beta) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8 + cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-gamma and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.
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