Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity
Arnab Ghosh, … , Vladimir Ponomarev, Marcel R.M. van den Brink
Arnab Ghosh, … , Vladimir Ponomarev, Marcel R.M. van den Brink
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2654-2662. https://doi.org/10.1172/JCI66301.
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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#x02013;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.

Authors

Arnab Ghosh, Yildirim Dogan, Maxim Moroz, Amanda M. Holland, Nury L. Yim, Uttam K. Rao, Lauren F. Young, Daniel Tannenbaum, Durva Masih, Enrico Velardi, Jennifer J. Tsai, Robert R. Jenq, Olaf Penack, Alan M. Hanash, Odette M. Smith, Kelly Piersanti, Cecilia Lezcano, George F. Murphy, Chen Liu, M. Lia Palomba, Martin G. Sauer, Michel Sadelain, Vladimir Ponomarev, Marcel R.M. van den Brink

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Figure 4

TRAIL+ T cells can eliminate residual host APCs.

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TRAIL+ T cells can eliminate residual host APCs. (A) Tissues from letha...
(A) Tissues from lethally irradiated CBF1 mice were harvested at designated time points and qPCR was performed for DR5. (B) DR5 was assessed by flow cytometry on splenocytes gated on CD11c+ DCs, CD11b+ macrophages, and B220+ B cells. Representative data from 2 independent experiments are shown (n = 3 per group). *P lt; 0.05. (C and D) Lethally irradiated WT or DR5 KO B6 recipients were reconstituted with 5 #x000d7; 106 cells per recipient of WT B10.BR TCD BM. Designated groups were treated with 1 #x000d7; 106 cells per recipient of B10.BR TRAIL+ T cells. Survival was monitored (C) and clinical GVHD scores were recorded weekly (D) in a blinded fashion. Graph representative of 2 independent experiments is shown. *P lt; 0.05; ***P lt; 0.001; ****P lt; 0.0001. mLN, mesenteric lymph node.