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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Research Article

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 1

TRAIL+ T cells are strong antitumor agents.

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TRAIL+ T cells are strong antitumor agents. (A) Representation of pLM-T...
(A) Representation of pLM-TRAIL-GFP construct: pLM-GFP-2A-TRAIL. (B) Prestimulated B6-derived T cells were transduced and transduction was measured by the expression of GFP. (C) TRAIL overexpression on transduced T cells was determined by flow cytometry. (D) TRAIL+ T cells mediate stronger killing against labeled LB27.4 targets in a 51Cr release cytolysis assay. Graphs representing 3 independent experiments are shown. (E) Lethally irradiated CBF1 recipients were reconstituted with 5 #x000d7; 106 cells per recipient of WT B6 TCD BM and inoculated with 2.5 #x000d7; 105 cells per recipient (upper panel) or 1 #x000d7; 105 cells per recipient of LB27.4 lymphoma cells (lower panel). Designated groups were treated with 0.5 #x000d7; 106 cells per recipient (upper panel) or 1 #x000d7; 106 cells per recipient (lower panel) of GFP+ or TRAIL+ T cells. (F) Transduced allogeneic GFP+ or TRAIL+ pre#x02013;T cells adoptively transferred into a syngeneic BMT model. RENCA tumor cells were inoculated s.c. 2 weeks after BMT. Tumor volume is expressed in centimeters cubed measured as 1/2 #x000d7; length #x000d7; (width)2. Pooled data from 2 independent experiments are depicted. *P lt; 0.05; **P lt; 0.01; ***P lt; 0.001; ****P lt; 0.0001. hPGK, human phosphoglycerate kinase promoter; pA, #x0201c;self-cleaving#x0201d; 2A peptides; WPRE, woodchuck hepatitis posttranscriptional regulatory element.