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

Sci Adv. 2022 Feb 4;8(5):eabi9533. doi: 10.1126/sciadv.abi9533. Epub 2022 Feb 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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

Supplementary concepts

  • Tuberous Sclerosis 1
  • Tuberous Sclerosis 2