Adoptive T-cell transfer to treat lymphangioleiomyomatosis

Fei Han, Emilia R. Dellacecca, Levi W. Barse, Cormac Cosgrove, Steven W. Henning, Christian M. Ankney, Dinesh Jaishankar, Alexander Yemelyanov, Vera P. Krymskaya, Daniel F. Dilling, I. Caroline Le Poole*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with neoplastic, smooth muscle-like cells that feature neuroendocrine cell markers. The disease preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic mutations underlying LAM, we cultured Tsc22/2 kidney tumor cells from aged Tsc2 heterozygous mice and generated a stable gp100-expressing cell line by lentiviral transduction. T cells were isolated from major histocompatibility complex-matched TCR transgenic pmel-1 mice to measure cytotoxicity in vitro, and 80% cytotoxicity was observed within 48 hours. Antigen-specific cytotoxicity was likewise observed using pmel-1 TCR-transduced mouse T cells, suggesting that transgenic T cells may likewise be useful to treat LAM in vivo. On intravenous injection, slow-growing gp1001 LAM-like cells formed lung nodules that were readily detectable in severe combined immunodeficient/beige mice. Adoptive transfer of gp100-reactive but not wild-type T cells into mice significantly shrunk established lung tumors, even in the absence of anti-PD-1 therapy. These results demonstrate the treatment potential of adoptively transferred T cells to eliminate pulmonary lesions in LAM.

Original languageEnglish (US)
Pages (from-to)793-804
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume62
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Adoptive T cell transfer
  • Gp100
  • Lymphangioleiomyomatosis
  • T cell receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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