Despite substantial progress in lung cancer immunotherapy, the overall response rate in KRAS-mutant lung adenocarcinoma (ADC) patients remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of anti-tumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused sgRNA library, and performed an in vivo CRISPR screen in a KrasG12D/P53-/- (KP) lung ADC model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T cell activation in combination with anti-PD-1. Our results provide rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy.
Authors: Fei Li, Qingyuan Huang, Troy A Luster, Hai Hu, Hua Zhang, Wai-Lung Ng, Alireza Khodadadi-Jamayran, Wei Wang, Ting Chen, Jiehui Deng, Michela Ranieri, Zhaoyuan Fang, Val Pyon, Catriona M. Dowling, Ece Bagdatlioglu, Christina Almonte, Kristen Labbe, Heather Silver, Alexandra R Rabin, Kandarp Jani, Aristotelis Tsirigos, Thales Papagiannakopoulos, Peter S. Hammerman, Vamsidhar Velcheti, Gordon J. Freeman, Jun Qi, George Miller and Kwok-Kin Wong
Cancer Discovery, in press.