WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC
Hirokazu Taniguchi, Rebecca Caeser, Shweta S. Chavan, Yingqian A. Zhan, Andrew Chow, Parvathy Manoj, Fathema Uddin, Hidenori Kitai, Rui Qu, Omar Hayatt, Nisargbhai Shah, Álvaro Quintanal Villalonga, Viola Allaj, Evelyn M. Nguyen, Joseph M. Chan, Adam O. Michel, Hiroshi Mukae, Elisa de Stanchina, Charles M. Rudin, Triparna Sen
Abstract
cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ 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.