Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer.

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 KrasG12D/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.

• Authors: 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
• Journal: Science advances (Sci Adv) Vol. 8 Issue 5 Pg. eabi9533 (02 04 2022) ISSN: 2375-2548 [Electronic] United States
• PMID: 35119931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• Immune Checkpoint Inhibitors
• TSC1 protein, human
• TSC2 protein, human
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein

Topics

• Animals
• B7-H1 Antigen
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Tuberous Sclerosis (drug therapy, genetics, metabolism)
• Tuberous Sclerosis Complex 1 Protein (metabolism)
• Tuberous Sclerosis Complex 2 Protein (metabolism)
• Tumor Microenvironment (genetics)