Adoptive T-Cell Transfer to Treat Lymphangioleiomyomatosis.

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.

Molecular properties of gp100-reactive T-cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells.

To study the contribution of T-cell receptors (TCR) to resulting T-cell responses, we studied three different human αß TCRs, reactive to the same gp100-derived peptide presented in the context of HLA-A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen-induced IFN-γ responses, which correlated with TCR affinity for peptide-MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL-17A release. Importantly, in vivo, SILv44-transgenic T cells mediated superior antitumor responses to 888-A2 + human melanoma tumor cells upon adoptive transfer into tumor-challenged mice while maintaining IL-17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T-cell receptor in defining host T-cell physiology than traditionally assumed, while parameters beyond IFN-γ secretion and TCR affinity ultimately determine the reactivity of tumor-reactive T cells.