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 3

TRAIL+ T cells suppress GVHD.

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TRAIL+ T cells suppress GVHD. (A and B) Livers and small and large inte...
(A and B) Livers and small and large intestines from B6#x02192;CBF1 mice treated with GFP+ or TRAIL+ T cells were harvested on day 14 after BMT and skin was harvested on day 21 and scored for GVHD pathology. Representative micrographs are shown (original magnification, #x000d7;200 for liver, small and large intestines; and #x000d7;400 for skin). GVHD scores pooled from 2 independent experiments are shown (n = 8#x02013;10 per group). (C) Thymi from B6#x02192;CBF1 mice treated with GFP+ or TRAIL+ T cells were harvested on day 21 after BMT. Total cellularity was obtained from counts of live thymocyte suspension and numbers of DP T cells were derived from flow cytometric determination of CD4+CD8+ T cell proportions. Data pooled from 2 independent experiments are shown (n = 8#x02013;10 per group). (D and E) Lethally irradiated CBF1 recipients were reconstituted with 5 #x000d7; 106 cells per recipient of B6 TCD BM. Designated groups were treated with 0.5 #x000d7; 106 cells per recipient of GFP+ or TRAIL+ T cells mixed with nontransduced Luc+ T cells. Bioluminescence imaging of the transplanted mice was performed weekly (D) and flux was measured (E). Animals representative of 1 experiment (n = 7 per group) and flux pooled from 3 independent experiments are shown. (F) Lethally irradiated CBF1 recipients were reconstituted with 5 #x000d7; 106 cells per recipient of B6 TCD BM. Designated groups were treated with 0.5 #x000d7; 106 cells per recipient of GFP+ or TRAIL+ T cells mixed with nontransduced T cells (n = 10 per group). Survival was monitored daily. *P lt; 0.05; **P lt; 0.01; ****P lt; 0.0001. NS, not significant.