Open AccessAdoptive T-Cell Transfer to Treat Lymphangioleiomyomatosis
Author(s) -
Fei Han,
Emilia R. Dellacecca,
Levi Barse,
Cormac Cosgrove,
Steven W. Henning,
Christian Ankney,
Dinesh Jaishankar,
Alexander Yemelyanov,
Vera P. Krymskaya,
Daniel F. Dilling,
I. Caroline Le Poole
Publication year - 2020
Publication title -
american journal of respiratory cell and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.469
H-Index - 161
eISSN - 1535-4989
pISSN - 1044-1549
DOI - 10.1165/rcmb.2019-0117oc
Subject(s) - adoptive cell transfer , t cell receptor , lymphangioleiomyomatosis , biology , cancer research , t cell , immunology , antigen , transgene , medicine , lung , immune system , biochemistry , gene
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 Tsc2 -/- 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 gp100 + 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.