| First Author | Taniguchi H | Year | 2022 |
| Journal | Cell Rep | Volume | 39 |
| Issue | 7 | Pages | 110814 |
| PubMed ID | 35584676 | Mgi Jnum | J:349197 |
| Mgi Id | MGI:7284006 | Doi | 10.1016/j.celrep.2022.110814 |
| Citation | Taniguchi H, et al. (2022) WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC. Cell Rep 39(7):110814 |
| abstractText | 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. |
