Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity Journal Article
| Authors: | Ghosh, A.; Dogan, Y.; Moroz, M.; Holland, A. M.; Yim, N. L.; Rao, U. K.; Young, L. F.; Tannenbaum, D.; Masih, D.; Velardi, E.; Tsai, J. J.; Jenq, R. R.; Penack, O.; Hanash, A. M.; Smith, O. M.; Piersanti, K.; Lezcano, C.; Murphy, G. F.; Liu, C.; Palomba, M. L.; Sauer, M. G.; Sadelain, M.; Ponomarev, V.; van den Brink, M. R. M. |
| Article Title: | Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity |
| Abstract: | Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. Copyright © 2013, American Society for Clinical Investigation. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 123 |
| Issue: | 6 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2013-06-03 |
| Start Page: | 2654 |
| End Page: | 2662 |
| Language: | English |
| DOI: | 10.1172/jci66301 |
| PROVIDER: | scopus |
| PMCID: | PMC3668849 |
| PUBMED: | 23676461 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 1 July 2013" - "CODEN: JCINA" - "Source: Scopus" |
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