Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis

Am J Respir Cell Mol Biol. 2018 Dec;59(6):723-732. doi: 10.1165/rcmb.2018-0123OC.


Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-γ. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti-PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1/PD-L1-mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.

Keywords: PD-1; TSC2; human; mTOR; torin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Case-Control Studies
  • Cell Proliferation
  • Disease Models, Animal
  • Humans
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lymphangioleiomyomatosis / drug therapy
  • Lymphangioleiomyomatosis / immunology
  • Lymphangioleiomyomatosis / metabolism*
  • Lymphangioleiomyomatosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • Tuberous Sclerosis / drug therapy
  • Tuberous Sclerosis / immunology
  • Tuberous Sclerosis / metabolism*
  • Tuberous Sclerosis / pathology
  • Up-Regulation


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse

Supplementary concepts

  • Tuberous Sclerosis 2