Loss of <i>TSC1/TSC2</i> sensitizes immune checkpoint blockade in non–small cell lung cancer

Abstract

Tuberous sclerosis complex subunit 1 (<i>TSC1</i>) and 2 (<i>TSC2</i>) are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine <i>Kras^G12D</i>/<i>Trp53^-/-</i> (KP) model identified <i>Tsc1</i> and <i>Tsc2</i> 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. <i>TSC1</i> or <i>TSC2</i> knockout (KO) promoted the transcriptional and membrane expression of PD-L1 in cell lines. <i>TSC2</i>-deficient tumors manifested an inflamed microenvironment in patient samples and The Cancer Genome Atlas dataset. In syngeneic murine models, KP-<i>Tsc2</i>-KO tumors showed notable response to anti-PD-1 antibody treatment, but <i>Tsc2</i>-wild-type tumors did not. Patients with <i>TSC1</i>/<i>TSC2</i>-mutant NSCLC receiving immune checkpoint blockade (ICB) had increased durable clinical benefit and survival. Collectively, <i>TSC1</i>/<i>TSC2</i> loss defines a distinct subtype of NSCLC characterized as inflamed tumor microenvironment and superior sensitivity to ICB.