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Flt-3L Expansion of Recipient Cd8a Dendritic Cells Deletes Alloreactive

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Flt-3L Expansion of Recipient Cd8a Dendritic Cells Deletes Alloreactive Published OnlineFirst January 24, 2018; DOI: 10.1158/1078-0432.CCR-17-2148 Cancer Therapy: Preclinical Clinical Cancer Research Flt-3L Expansion of Recipient CD8aþ Dendritic Cells Deletes Alloreactive Donor T Cells and Represents an Alternative to Posttransplant Cyclophosphamide for the Prevention of GVHD Kate A. Markey1,2,3, Rachel D. Kuns1, Daniel J. Browne1, Kate H. Gartlan1,3, Renee J. Robb1, J. Paulo Martins1, Andrea S. Henden1,2,3, Simone A. Minnie1, Melody Cheong1, Motoko Koyama1, Mark J. Smyth1,3, Raymond J. Steptoe4, Gabrielle T. Belz5, Thomas Brocker6, Mariapia A. Degli-Esposti7,8, Steven W. Lane1,2,3, and Geoffrey R. Hill1,2 Abstract Purpose: Allogeneic bone marrow transplantation (BMT) pro- kinase-3 ligand (Flt-3L) treatment to the current clinical strat- vides curative therapy for leukemia via immunologic graft-versus- egy of posttransplant cyclophosphamide (PT-Cy) therapy. Our leukemia (GVL) effects. In practice, this must be balanced against results demonstrate superior protection from GVHD with the life threatening pathology induced by graft-versus-host disease immunomodulatory Flt-3L approach, and similar attenuation (GVHD). Recipient dendritic cells (DC) are thought to be impor- of GVL responses with both strategies. Strikingly, Flt-3L treat- tant in the induction of GVL and GVHD. ment permitted maintenance of the donor polyclonal T-cell Experimental Design: We have utilized preclinical models pool, where PT-Cy did not. of allogeneic BMT to dissect the role and modulation of Conclusions: These data highlight pre-transplant Flt-3L recipient DCs in controlling donor T-cell–mediated GVHD therapy as a potent new therapeutic strategy to delete allo- and GVL. reactive T cells and prevent GVHD, which appears particularly þ Results: We demonstrate that recipient CD8a DCs promote well suited to haploidentical BMT where the control of infec- activation-induced clonal deletion of allospecific donor tion and the prevention of GVHD are paramount. Clin Cancer T cells after BMT. We compared pretransplant fms-like tyrosine Res; 24(7); 1604–16. Ó2018 AACR. Introduction these two immunologic phenomena remains the ultimate goal in the field. Furthermore, retaining functionality within the Understanding the modifiable determinants of alloreactivity nonalloreactive T-cell pool is paramount for the prevention of is critical for the design of rational strategies to prevent and severe infection that remains responsible for both short- and treat graft-versus-host disease (GVHD) after allogeneic bone long-term mortality after BMT. marrow transplantation (BMT). The elimination of GVHD Outside of selecting optimally matched donors, the preven- must be balanced against maintenance of protective graft- tion of pathogenic alloreactive T-cell responses (i.e., GVHD) versus-leukemia (GVL) effects and meaningful separation of relies on T-cell depletion or pharmacologic immune suppres- sion, usually with calcineurin inhibitors (i.e., cyclosporin or tacrolimus). Posttransplant cyclophosphamide (PT-Cy), which 1 2 QIMR Berghofer Medical Research Institute, Brisbane, Australia. Royal Brisbane is thought to eliminate activated, proliferating alloreactive and Women's Hospital, Brisbane, Australia. 3School of Medicine, University of Queensland, Herston, Queensland, Australia. 4University of Queensland Dia- donor T cells (while sparing regulatory T-cell populations) is mantina Institute, Translational Research Institute, Brisbane, Australia. 5Walter also highly effective in reducing the incidence of chronic GVHD and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. after haploidentical BMT (1–5). 6Institute for Immunology, Ludwig-Maximilians Universitat, Munich, Germany. Retrospective data suggest that PT-Cy may be superior to 7 Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western standard immune suppression (with or without anti-thymocyte 8 Australia. Immunology and Virology Program, Centre for Ophthalmology and globulin) with regard to the prevention of chronic GVHD after Visual Science, University of Western Australia, Crawley, Western Australia. unrelated donor transplantation (6) although this requires con- Note: Supplementary data for this article are available at Clinical Cancer firmation in prospective randomized studies. Interestingly, the Research Online (http://clincancerres.aacrjournals.org/). effect of PT-Cy on leukemia relapse is unclear, and importantly, Corresponding Author: Kate A. Markey, Bone Marrow Transplantation Labo- no prospective studies to date have been sufficiently powered ratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia. Phone: to analyze relapse after BMT using PT-Cy compared with stan- 617-3362-0290; Fax: 617-3845-3509; E-mail: [email protected] dard immune suppression. With the expanding role of alternate doi: 10.1158/1078-0432.CCR-17-2148 donor transplantation, it is critically important to understand Ó2018 American Association for Cancer Research. the drivers of early T-cell responses that characterize GVL effects 1604 Clin Cancer Res; 24(7) April 1, 2018 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 24, 2018; DOI: 10.1158/1078-0432.CCR-17-2148 Recipient DCs Drive Deletion of Donor Ag-specific T Cells þ À/À bm1 (lacking in CD8a DC, (17)], b2m , Bm1 (H-2K ), and Translational Relevance bm1 Bm1.ActmOVA (H-2K and ubiquitous ovalbumin expression Graft-versus-host disease (GVHD) is a major barrier to driven off the b-actin promoter). Female mice at 8 to 12 weeks of successful allogeneic bone marrow transplantation, a proce- age were used throughout the study. dure offering curative potential to patients with hematologic malignancies and marrow failure syndromes. In our preclin- Bone marrow chimeras À À ical models, pretreatment with Flt-3L (pre-T Flt-3L) expands For IRF8 / chimeras, bone marrow was harvested from þ À À recipient CD8a DCs that subsequently activate and delete IRF8 / mice and 5  106 bone marrow cells/mouse transferred antigen-specific donor T cells, an effect similar to that seen with by intravenous injection into lethally irradiated (1,000 cGy) B6. posttransplant cyclophosphamide (PT-Cy). Pre-T Flt-3L offers WT or B6.CD45.1 (PTprca) recipients and allowed to reconstitute protection from GVHD while facilitating the maintenance of for 3 months prior to second transplantation. third-party reactive donor T cells. Pre-T Flt-3L, like PT-Cy, resulted in marked reductions in graft-versus-leukemia effects. Bone marrow transplantation, leukemia induction, and As Flt-3L has shown acceptable safety profiles in phase I/II treatment schedules clinical trials, this approach to prevent GVHD is readily B6 recipients of C3HSw grafts received 1  106 FACS purified þ À þ testable. (CD90.2 /CD4 )CD8 Tcellsand5 106 bone marrow cells. Where T cell depleted (TCD) bone marrow controls were included, cells were prepared using an antibody incubation followed by complement depletion as described previously and infectious immunity, such that they may be targeted for (18). In the C3H.Sw model, donor mice were immunized via therapeutic benefit. intraperitoneal injection with B6 splenocytes 2 weeks prior to  6 It is now clear that recipient antigen-presenting cells (APC), transplantation. B6D2F1 recipients received 5 10 TCD bone þ – fi þ both hematopoietic and nonhematopoietic, initiate alloreac- marrow cells either magnetic bead puri ed CD8 T cells (MACS-purified according to the manufacturer's instructions, tive donor T-cell responses and GVHD (7), while reconstituting þ Miltenyi Biotec), CD3 T cells (as previously described; ref. 18), donor DCs determine final GVHD severity (8, 9). As yet, no þ preventive or therapeutic approaches have been developed to or OT-I Tg CD8 T cells in doses as stated. OT-I were MACS- fi specifically target the antigen presentation component of T-cell puri ed from spleen and lymph nodes. Where OT-I T cells were fi activation. With regard to GVL responses, recipient APC (puta- transferred to read out antigen-speci c responses, MHC class – fi b À/À tively dendritic cells, but this is as yet unproven) are thought to I de cient ( 2m ) bone marrow was used to exclude any determine the magnitude of responses (10), with donor APC contribution of indirect antigen presentation by donor APC. playing a limited role (11). Total body irradiation (TBI) doses were as follows: B6 back- þ Given the important effects of CD8 TcellsinHLA-matched ground, 900 cGy in the presence of DT treatment and 1,000 cGy þ clinical transplantation (12), we have focused on CD8 T cell- otherwise; B6D2F1 mice, 1,100 cGy; Balb/B mice 400 cGy (in fl driven mouse models of allogeneic BMT. Here, we have defined conjunction with 2 mg udarabine d-4 to d-2). the contribution of dendritic cells (DC) to GVL effects, and For in vivo depletion of DTR-expressing DCs, diphtheria explored the influence of recipient DCs on donor T-cell acti- toxin from Corynebacterium diphtheriae (Sigma Aldrich) was vation following allogeneic BMT in models that recapitulate administered intraperitoneally at 160 ng per dose on day À À both HLA matched and haploidentical transplantation in the 2, 1, 0, 1, and 2 for day 3 analyses and continued on day þ clinic. Surprisingly, we find that recipient CD8a DCs potently 5, 7, 9, for day 10 analyses. Primary leukemia cells were induce antigen-specific deletion of donor cytotoxic T cells generated using the expression of the human oncogenes þ (CTL). We demonstrate that this
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