IFN-γ and Fas Ligand Are Required for Graft-versus-Tumor Activity against Renal Cell Carcinoma in the Absence of Lethal Graft-versus-Host Disease

Ramirez-Montagut, Teresa; Chow, Andrew; Kochman, Adam A.; Smith, Odette M.; Suh, David; Sindhi, Hamad; Lu, Sydney X.; Borsotti, Chiara; Grubin, Jeremy; Patel, Niral; Terwey, Theis H.; Kim, Theo D.; Heller, Glenn; Murphy, Gëorge F.; Liu, Chen; Alpdoğan, Önder; Brink, Marcel R.M. van den

doi:10.4049/jimmunol.179.3.1669

Cited by 20 publications

(22 citation statements)

References 55 publications

(30 reference statements)

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“…Together, these results suggest that IFN-g and FasL might have accounted for a part of the enhanced GVT activity delivered by GzmB 2/2 CD8 + T cells. This notion is consistent with previous studies showing that IFN-g and FasL contribute to CD8 + T cell-mediated GVT activity without causing severe GVHD (35)(36)(37).…”

Section: Cd8supporting

confidence: 82%

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Bian

Ding

Leigh

et al. 2013

The Journal of Immunology

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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and other malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the treatment. Using multiple tumor models and diverse donor–host combinations, we have studied the role of granzyme B (GzmB) in GVT effect. We first confirmed previous findings that GzmB deficiency diminished the ability of a high dose of CD8+ T cells to cause lethal graft-versus-host disease. However, when GVT studies were performed using a moderate cell dose that the hosts could tolerate, GzmB−/− CD8+ T cells demonstrated a significantly enhanced GVT effect. GzmB-mediated, activation-induced cell death in wild-type CD8+ T cells was found responsible for their reduced GVT activity. Conversely, GzmB−/− CD8+ T cells exhibited enhanced expansion, skewed toward an effector or effector memory phenotype, and produced higher amounts of IFN-γ and Fas ligand that might contribute to GzmB-independent tumor control. These findings demonstrate for the first time, to our knowledge, that GzmB-mediated damage of CD8+ T cells impairs the desired GVT effect. This study suggests that inhibiting donor-derived GzmB function may represent a promising strategy to improve GVT effect without exacerbating graft-versus-host disease.

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Section: Cd8supporting

confidence: 82%

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Bian

Ding

Leigh

et al. 2013

The Journal of Immunology

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“…In this study, we thus evaluated whether TRAIL overexpression could result in aggravated thymic GVHD, but did not find evidence for this. One possible explanation is that physiological expression of TRAIL by alloactivated T cells develops with the coexpression of other cytolytic ligands, and isolated overexpression of TRAIL may not be adequate to exacerbate thymic GVHD without the contribution of multiple other cytolytic mediators downstream of the alloreactive activation known to play roles in GVHD and GVT activity (23).…”

Section: Discussionmentioning

confidence: 99%

Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

Ghosh¹,

Dogan²,

Moroz³

et al. 2013

J. Clin. Invest.

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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.

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“…IFN-g upregulates Fas expression on RENCA cells, which induces their elimination by Fas ligand-expressing CD8 þ T-cells. 13 It is also possible that NK cells may have a role in anti-tumor activity in RENCA-bearing mice. 17,18 Post transplant CY infusion enhanced tolerization of T-cells, which resulted in a reduced risk of GVHD while preserving GVT effect to RENCA cells in murine models.…”

Section: Discussionmentioning

confidence: 99%

“…This GVT activity was dependent on IFN-g and FasL expression on CD8 þ T-cells. 13 The data suggest that CD8 þ T-cells produce IFN-g, which upregulates Fas on RENCA cells. This Fas expression on RENCA cells facilitates tumor elimination from the host via Fas ligand-expressing allo-activated CD8 þ T-cells.…”

Section: Introductionmentioning

confidence: 99%

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Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

Budak‐Alpdoğan

Sauter

Bailey

et al. 2013

Bone Marrow Transplant

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Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus-tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2K b/d ) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2K b/k ) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 Â 10 5 ) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1-CB6F1) and parent-F1 (B6-CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-g-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma. Keywords: renal cell cancer; animal models; graft-versus-tumor effect; GVHD; haploidentical hematopoietic SCT INTRODUCTION Allogeneic hematopoietic SCT (HSCT) has been successfully used for treatment of hematological malignancies. However, this approach has not been used for patients with solid tumors, even for tumor types where immune modulatory treatments are widely used. Anti-tumor or graft-versus-tumor (GVT) effects of the graft contribute to the elimination of the residual tumor cells in certain types of malignancies. For the most part, the transplant community does not consider patients with solid tumors to be good candidates for allogeneic HSCT due to transplant-related mortality and late reconstitution of immune competency. However, pioneering studies suggest that non-myeloablative allogeneic HSCT for advanced renal cell cancer (RCC) might induce sustained regression of metastatic RCC in patients who have failed conventional therapies. [1][2][3][4][5] Seventy-four patients with advanced RCC underwent allogeneic HSCT following non-myeloablative conditioning, and 39% of the patients were responsive, including 9.5% of patients that underwent a CR. 5 The median tumor response occurred at 133 days after allogeneic HSCT and there were detectable RCC-reactive CD8 T-cells in responsive patients. 5 The onset of RCC regression after non-myeloablative HSCT is delayed by several months, which suggests that GVT activity of MHC-matched HSCT is a slow process and may not be sufficient to control aggressive disease. In a European study, OS was found to be 30% at 2 years after HSCT. 3 However, CALGB data did not support these observations and did not re...

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IFN-γ and Fas Ligand Are Required for Graft-versus-Tumor Activity against Renal Cell Carcinoma in the Absence of Lethal Graft-versus-Host Disease

Cited by 20 publications

References 55 publications

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma

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