Synapse - WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC

WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC Journal Article

Authors:	Taniguchi, H.; Caeser, R.; Chavan, S. S.; Zhan, Y. A.; Chow, A.; Manoj, P.; Uddin, F.; Kitai, H.; Qu, R.; Hayatt, O.; Shah, N. S.; Quintanal Villalonga, Á.; Allaj, V.; Nguyen, E. M.; Chan, J.; Michel, A. O.; Mukae, H.; de Stanchina, E.; Rudin, C. M.; Sen, T.
Article Title:	WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC
Abstract:	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.
Keywords:	gene; carboplatin; repair; stage; kinase; cell lung-cancer; quantification; phase-i; azd1775; targeting dna-damage
Journal Title:	Cell Reports
Volume:	39
Issue:	7
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2022-05-17
Start Page:	110814
Language:	English
ACCESSION:	WOS:000804704200003
DOI:	10.1016/j.celrep.2022.110814
PROVIDER:	wos
PUBMED:	35584676
PMCID:	PMC9449677
Notes:	Article -- Source: Wos