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

Qingyuan Huang1,2, Fei Li3, Hai Hu4

  • 1Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.

Science Advances
|February 4, 2022
PubMed

Insights

Mutations in TSC1 or TSC2 genes in non-small cell lung cancer (NSCLC) enhance antitumor immunity. This discovery suggests TSC1/TSC2-mutant NSCLC may respond better to immune checkpoint blockade therapies.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) genes TSC1 and TSC2 are frequently mutated in non-small cell lung cancer (NSCLC).
  • The impact of TSC1/TSC2 mutations on antitumor immunity in NSCLC remains largely unexplored.

Purpose of the Study:

  • To investigate the role of TSC1 and TSC2 in regulating programmed cell death ligand 1 (PD-L1) expression.
  • To determine the effect of TSC1/TSC2 loss on sensitivity to anti-PD-1 therapy in NSCLC.

Main Methods:

  • CRISPR screening in a murine Kras/Trp53 (KP) model.
  • In vitro and in vivo experiments assessing PD-L1 expression and anti-PD-1 treatment response.
  • Analysis of patient samples and The Cancer Genome Atlas (TCGA) dataset for tumor microenvironment characteristics.

Main Results:

  • TSC1 or TSC2 knockout (KO) significantly increased PD-L1 expression in NSCLC cell lines.
  • TSC2-deficient tumors exhibited an inflamed tumor microenvironment.
  • KP-Tsc2-KO tumors showed a strong response to anti-PD-1 therapy, unlike Tsc2-wild-type tumors.
  • Patients with TSC1/TSC2-mutant NSCLC demonstrated improved outcomes with immune checkpoint blockade (ICB).

Conclusions:

  • Loss of TSC1/TSC2 promotes PD-L1 expression and an inflamed tumor microenvironment in NSCLC.
  • TSC1/TSC2 mutations identify a NSCLC subtype with enhanced sensitivity to anti-PD-1 therapy and ICB.

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