Loss of <i>TSC1/TSC2</i> sensitizes immune checkpoint blockade in non–small cell lung cancer
Qingyuan Huang, Fei Li, Hai Hu, Zhaoyuan Fang, Zhendong Gao, Guozhan Xia, Wai‐Lung Ng, Alireza Khodadadi‐Jamayran, Ting Chen, Jiehui Deng, Hua Zhang, Christina Almonte, Kristen Labbe, Han Han, Ke Geng, Sittinon Tang, Gordon J. Freeman, Yuan Li, Haiquan Chen, Kwok‐Kin Wong
Abstract
Tuberous sclerosis complex subunit 1 ( TSC1 ) and 2 ( TSC2 ) are frequently mutated in non–small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine Kras G12D / Trp53 −/− (KP) model identified Tsc1 and Tsc2 as potent regulators of programmed cell death ligand 1 (Pd-l1) expression in vitro and sensitivity to anti–programmed cell death receptor 1 (PD-1) treatment in vivo. TSC1 or TSC2 knockout (KO) promoted the transcriptional and membrane expression of PD-L1 in cell lines. TSC2 -deficient tumors manifested an inflamed microenvironment in patient samples and The Cancer Genome Atlas dataset. In syngeneic murine models, KP- Tsc2 -KO tumors showed notable response to anti–PD-1 antibody treatment, but Tsc2 –wild-type tumors did not. Patients with TSC1 / TSC2 -mutant NSCLC receiving immune checkpoint blockade (ICB) had increased durable clinical benefit and survival. Collectively, TSC1 / TSC2 loss defines a distinct subtype of NSCLC characterized as inflamed tumor microenvironment and superior sensitivity to ICB.