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Terry J. Fry - One of the best experts on this subject based on the ideXlab platform.
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
2016Co-Authors: Meghaan P. Walsh, Brynn Duncan, Shannon Larabee, Aviva Krauss, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro-mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robus
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
PloS one, 2013Co-Authors: Meghaan P. Walsh, Brynn B. Duncan, Shannon Larabee, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Aviva C Krauss, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.
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Alloreactivity Directed Against the Widely Distributed HY Antigen Impairs Antitumor Immunity and Results in T-Cell Dysfunction
Blood, 2011Co-Authors: Jessica C. Shand, Christian M. Capitini, Haiying Qin, Nicole Nasholm, Brynn B. Duncan, Terry J. FryAbstract:Abstract 2964 INTRODUCTION: The curative potential of allogeneic transplant for high-risk malignancy is based on the observation that alloreactivity can result in a clinically significant graft-versus-tumor (GVT) effect. However, we have observed that alloreactivity directed against non-tumor restricted miHA's reduces quantitative responses to vaccines targeting tumor-specific Antigens. The relative impact of the GVHD-mediating Antigen on the potency of the GVT response when the Antigen is shared has not been well studied. METHODS: A murine allotransplant system in which the clinically relevant GVHD Antigen HY drives both graft-versus-host disease and the antitumor response was utilized. Following lethal irradiation, combinations of B6 male (HY-expressing) and female (HY-naive) donors and recipients were used in T-cell depleted bone marrow transplants to control for HY expression in hematopoetic and non-hematopoetic compartments. Delayed donor lymphocyte infusion (DLI) with female HY-specific transgenic T-cells was then performed which allowed tracking of Antigen-specific cells. Mice were subsequently challenged with an immunogenic HY-expressing tumor (MB49). In tumor protection studies, transplant recipients received a male dendritic cell vaccine at the time of DLI. Recipients were monitored for clinical GVHD scoring, weight loss, tumor-free and overall survival. Surface phenotyping of HY-specific CD8 T cells from recipient bone marrow, tumor-draining lymph node (LN) and spleen was performed serially by flow cytometry using congenic markers. Statistical analyses were performed using paired Student t-tests and Kaplan-Meier survival estimates. RESULTS: Transplantation of female marrow and HY-specific T cells into male recipients produces a mild HY-targeted GVHD, indicated by weight loss and skin GVHD scores. Female recipients of female marrow and HY-specific DLI had 100% survival following HY-expressing tumor challenge. In contrast, male recipients had only 20 +/− 4.7% tumor-free survival (p
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alloreactivity directed against the widely distributed HY Antigen impairs antitumor immunity and results in t cell dysfunction
Blood, 2011Co-Authors: Jessica C. Shand, Christian M. Capitini, Haiying Qin, Nicole Nasholm, Brynn B. Duncan, Terry J. FryAbstract:Abstract 2964 INTRODUCTION: The curative potential of allogeneic transplant for high-risk malignancy is based on the observation that alloreactivity can result in a clinically significant graft-versus-tumor (GVT) effect. However, we have observed that alloreactivity directed against non-tumor restricted miHA's reduces quantitative responses to vaccines targeting tumor-specific Antigens. The relative impact of the GVHD-mediating Antigen on the potency of the GVT response when the Antigen is shared has not been well studied. METHODS: A murine allotransplant system in which the clinically relevant GVHD Antigen HY drives both graft-versus-host disease and the antitumor response was utilized. Following lethal irradiation, combinations of B6 male (HY-expressing) and female (HY-naive) donors and recipients were used in T-cell depleted bone marrow transplants to control for HY expression in hematopoetic and non-hematopoetic compartments. Delayed donor lymphocyte infusion (DLI) with female HY-specific transgenic T-cells was then performed which allowed tracking of Antigen-specific cells. Mice were subsequently challenged with an immunogenic HY-expressing tumor (MB49). In tumor protection studies, transplant recipients received a male dendritic cell vaccine at the time of DLI. Recipients were monitored for clinical GVHD scoring, weight loss, tumor-free and overall survival. Surface phenotyping of HY-specific CD8 T cells from recipient bone marrow, tumor-draining lymph node (LN) and spleen was performed serially by flow cytometry using congenic markers. Statistical analyses were performed using paired Student t-tests and Kaplan-Meier survival estimates. RESULTS: Transplantation of female marrow and HY-specific T cells into male recipients produces a mild HY-targeted GVHD, indicated by weight loss and skin GVHD scores. Female recipients of female marrow and HY-specific DLI had 100% survival following HY-expressing tumor challenge. In contrast, male recipients had only 20 +/− 4.7% tumor-free survival (p<0.0001), despite receiving HY-reactive female marrow and HY-specific DLI. Administration of an HY-expressing male dendritic cell vaccine did not improve either tumor growth velocity or tumor-free survival in male recipients. Despite a poor antitumor response in males, expression of HY on nonhematopoetic tissues produced a significant expansion of HY specific T-cells following DLI, regardless of tumor-bearing status (30.5 −77.4% total CD8 from spleen, draining LN and marrow, vs 0.01–1% from female recipient controls, p<0.0001). This suggested that impaired tumor control was due to dysfunction, rather than deletion, of HY-specific T cells. Indeed, nearly 100% of HY-specific CD8 isolated from the spleen, tumor-draining lymph node, and bone marrow of male recipients expressed high levels of PD-1, a phenomenon observed at all time points in tumor-bearing and non tumor-bearing male recipients with HY-directed GVHD. Non-HY specific CD8 cells did not express PD-1 (p<0.0001). Further, HY-specific CD8 from spleen and tumor-draining LN of male recipients display a significantly increased percentage of CD44+CD62L- effector memory (72.4 +/− 17.2%) vs. CD44+CD62L+ central memory (15.9 +/− 9.7%, p= 0.006) cells compared to non-HY specific CD8 cells (26.5% +/− 2.8 % vs. 28.2 +/− 12.7%, p= 0.52) from male and female recipient controls. CONCLUSIONS: In an experimental system where HY is expressed on both recipient nonhematopoetic tissue and tumor, HY-directed alloreactivity impairs the antitumor response despite Antigen-specific DLI and effective vaccination. Characterization of alloreactive CD8 T cells in this setting reveals a persistence of effector memory and high levels of PD-1 expression, which suggest T-cell dysfunction as a possible mechanism. Further studies of T-cell dysfunction in this model may identify targets for therapeutic blockade following adoptive immunotherapy with particular relevance to those clinical situations where GVHD does not enhance GVT. Disclosures: No relevant conflicts of interest to declare.
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Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors
Blood, 2008Co-Authors: Meghaan Walsh, Jessica P. E. Davis, Su Young Kim, Martin Guimond, Aviva C Krauss, Crystal L. Mackall, Terry J. FryAbstract:BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro , it exhibits potent antitumor effects in vivo . We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility Antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY Antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression. METHODS: B6 female mice were inoculated subcutaneously with MB49 (10 6 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×10 6 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY Antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naive mice and injected intravenously into Rag1−/− recipients (1.2×10 6 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×10 5 cells). RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo . Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors. CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.
Meghaan P. Walsh - One of the best experts on this subject based on the ideXlab platform.
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
2016Co-Authors: Meghaan P. Walsh, Brynn Duncan, Shannon Larabee, Aviva Krauss, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro-mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robus
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
PloS one, 2013Co-Authors: Meghaan P. Walsh, Brynn B. Duncan, Shannon Larabee, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Aviva C Krauss, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.
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radiofrequency ablation induces Antigen presenting cell infiltration and amplification of weak tumor induced immunity
Radiology, 2009Co-Authors: Sergio Dromi, Meghaan P. Walsh, Sarah Herby, Bryan Traughber, Jianwu Xie, Karun Sharma, Kiran Sekhar, Alfred Chun Shui Luk, David J Liewehr, Matthew R DreherAbstract:Purpose: To evaluate the influence of subtotal radiofrequency (RF) ablation on a tumor-specific immune response in a murine tumor model and to explore the role of intratumoral dendritic cells (ITDCs) in mediating this effect. Materials and Methods: Animal work was performed according to an approved protocol and in compliance with the National Cancer Institute Animal Care and Use Committee guidelines and regulations. A murine urothelial carcinoma (MB49) model expressing the male minor histocompatibility (HY) Antigen was inoculated subcutaneously in female mice. Fourteen days later, splenic T cells were analyzed with enzyme-linked immunosorbent spot for HY immune response (n = 57). In subsequent experiments, mice were randomized into control (n = 7), RF ablation, ITDC (n = 9), and RF ablation + ITDC (n = 9) groups and monitored for tumor growth. Eleven days after treatment, tumors were harvested for histologic and immunohistochemical analysis. Animals demonstrating complete tumor regression were rechallenged in the contralateral flank. Results: Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY Antigens and tumor regression. RF ablation, ITDC, and combined groups demonstrated similar levels of Antigen-presenting cell infiltration; all groups demonstrated greater levels of infiltration compared with untreated controls. ITDC injection also resulted in tumor regression. However, combination therapy did not enhance tumor regression when compared with either treatment alone. Rechallenged mice in RF ablation, ITDC, and combination groups demonstrated significant tumor growth inhibition compared with controls. Conclusion: Subtotal RF ablation treatment results in enhanced systemic antitumor T-cell immune responses and tumor regression that is associated with increased dendritic cell infiltration. ITDC injection mimics the RF ablation effect but does not increase immune responses when injected immediately after RF ablation. © RSNA, 2009
Martin Guimond - One of the best experts on this subject based on the ideXlab platform.
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
2016Co-Authors: Meghaan P. Walsh, Brynn Duncan, Shannon Larabee, Aviva Krauss, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro-mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robus
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
PloS one, 2013Co-Authors: Meghaan P. Walsh, Brynn B. Duncan, Shannon Larabee, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Aviva C Krauss, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.
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Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors
Blood, 2008Co-Authors: Meghaan Walsh, Jessica P. E. Davis, Su Young Kim, Martin Guimond, Aviva C Krauss, Crystal L. Mackall, Terry J. FryAbstract:BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro , it exhibits potent antitumor effects in vivo . We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility Antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY Antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression. METHODS: B6 female mice were inoculated subcutaneously with MB49 (10 6 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×10 6 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY Antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naive mice and injected intravenously into Rag1−/− recipients (1.2×10 6 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×10 5 cells). RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo . Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors. CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.
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GVHD Abrogates T Cell Responses to Dendritic Cell Vaccines but Not Vaccine-Induced Proliferation.
Blood, 2007Co-Authors: Christian M. Capitini, Martin Guimond, Crystal L. Mackall, Terry J. FryAbstract:BACKGROUND: Allogeneic bone marrow transplant (BMT) is a potent form of immunotherapy against hematopoietic and potentially solid tumors, but relapse of malignancy and Graft versus Host Disease (GVHD) remain a major cause of morbidity and mortality. Dendritic cell (DC) vaccines represent a potential strategy to enhance the potency and efficacy of the Graft versus Tumor (GVT) effect without exacerbating GVHD, but little is known regarding the impact of the allogeneic BMT environment on vaccine responses. Previous work in our lab has shown that DC can effectively expand tumor-Antigen specific T cells following minor-mismatched allogeneic transplantation, resulting in delay of tumor growth. However, GVHD completely abrogates these responses. We HYpothesized that the mechanism behind the loss of DC vaccine responses was through diminished T cell proliferation in the setting of GVHD. METHODS: We established a minor histocompatibility Antigen mismatched BMT model by transplanting B6 x C3H.SW (F1) tHYmectomized mice with either CD45.1+ B6 (allogeneic) or CD45.1+/45.2+ F1 (syngeneic) T cell-depleted bone marrow on day 0, followed by a donor lymphocyte infusion at day 14 to induce GVHD. On day 28, we adoptively transferred transgenic CD8+ (CD45.2, V beta 8.3+) or CD4+ (CD45.2, V beta 6+) T cells that only recognize components of the HY Antigen to avoid cross-reactivity with allogeneic Antigens. The T cells were labeled with CFSE prior to transfer to explore the impact of vaccine-induced proliferation in the presence or absence of GVHD. RESULTS: In the allogeneic BMT setting, both CD8+ and CD4+ HY-transgenic T cells given with a DC vaccine begin proliferating 5 days (CD8+ 40%, CD4+ 65% divided) after adoptive transfer. The syngeneic BMT vaccinated control mice show similar kinetics (CD8+ 38%, CD4+ 65% divided), suggesting GVHD does not decrease T cell proliferation. Interestingly, although HY transgenic T cells do not normally undergo homeostatic peripheral expansion (HPE) during lymphopenia, the CD4+ T cells proliferate in lymph nodes even in the absence of a vaccine (50% divided), but this was not observed in the respective syngeneic BMT unvaccinated control mice (0% divided). CONCLUSIONS: DC vaccines represent a strategy to improve the efficacy of the GVT response following allogeneic BMT, however, GVHD can abrogate DC vaccine responses. The negative impact of GVHD on vaccine responses does not appear to result from impaired DC vaccine-driven proliferation. Indeed, even in the absence of a vaccine, non-alloreactive CD4+ T cells proliferate via a mechanism that appears to be distinct from HPE. This data provides important insights towards optimizing Antigen-specific vaccines administered in the allogeneic BMT setting.
Eric Spierings - One of the best experts on this subject based on the ideXlab platform.
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Gene therapy with IgG-HY fusion proteins to reduce male-specific T-cell reactivity in vitro.
Human gene therapy, 2011Co-Authors: Miranda P. Dierselhuis, Ellen Schrama, David W. Scott, Eric SpieringsAbstract:Graft-versus-host disease is still a major complication in stem-cell transplantation. In HLA-identical stem-cell transplantation, mismatches in minor histocompatibility Antigens contribute to the development of graft-versus-host disease. As treatment of graft-versus-host disease with immunosuppressive drugs potentially also reduces the graft-versus-leukemia responses, Antigen-specific tolerance induction may be used to reduce graft-versus-host disease while leaving the graft-versus-leukemia responses intact. In mouse models, induction of Antigen-specific tolerance using IgG-Antigen-transduced B cells can prevent and ameliorate autoimmunity. In this study, the principle of the in vivo animal model has been applied to a human in vitro model wherein induction of tolerance against the HLA class II-restricted male-specific minor histocompatibility Antigen RPS4Y1 has been analyzed. T cells precultured in the presence of B cells expressing the IgG-coupled HY Antigen showed reduced responsiveness selectively against the minor HY Antigen RPS4Y1 in different in vitro protocols. These first observations serve as a basis for further studying and understanding the tolerizing potential of IgG constructs with human T cells.
Su Young Kim - One of the best experts on this subject based on the ideXlab platform.
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
2016Co-Authors: Meghaan P. Walsh, Brynn Duncan, Shannon Larabee, Aviva Krauss, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro-mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robus
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Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors
PloS one, 2013Co-Authors: Meghaan P. Walsh, Brynn B. Duncan, Shannon Larabee, Jessica P. E. Davis, Yongzhi Cui, Su Young Kim, Martin Guimond, William Bachovchin, Aviva C Krauss, Terry J. FryAbstract:Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY Antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.
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Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors
Blood, 2008Co-Authors: Meghaan Walsh, Jessica P. E. Davis, Su Young Kim, Martin Guimond, Aviva C Krauss, Crystal L. Mackall, Terry J. FryAbstract:BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro , it exhibits potent antitumor effects in vivo . We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility Antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY Antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression. METHODS: B6 female mice were inoculated subcutaneously with MB49 (10 6 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×10 6 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY Antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naive mice and injected intravenously into Rag1−/− recipients (1.2×10 6 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×10 5 cells). RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo . Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors. CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.