Ectopic activation of the miR-200c–EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy

Minggang Zhang, Zeguo Zhao, Yuri Pritykin, Margaret Hannum, Andrew C. Scott, Fengshen Kuo, Viraj Sanghvi, Timothy A. Chan, Venkatraman Seshan, Hans Guido Wendel, Andrea Schietinger, Michel Sadelain, Morgan Huse

Research output: Contribution to journalArticlepeer-review

Abstract

Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF). miR-200c elicited these changes by suppressing the transcription factor Zeb1 and thereby inducing genes characteristic of epithelial cells. Overexpression of one of these genes, Epcam, was sufficient to augment therapeutic T cell responses against both solid and liquid tumors. These results identify the miR-200c–EpCAM axis as an avenue for improving ACT and demonstrate that select genetic perturbations can produce phenotypically distinct T cells with advantageous therapeutic properties.

Original languageEnglish (US)
Article numbereabg4328
JournalScience Translational Medicine
Volume13
Issue number611
DOIs
StatePublished - Sep 15 2021

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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