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Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b+Gr1+ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-l-arginine methyl ester (l-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, l-NAME or sildenafil, and evaluated for CD11b+ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.Results: CD11b+Gr1high, CD11b+Gr1int, and CD11b+Gr1− cells differently accumulated in different organs and especially in the tumor of the two mouse models. l-NAME and sildenafil impaired the immunosuppressive function of CD11b+ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice.Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. Clin Cancer Res; 17(5); 1012–23. ©2011 AACR.

Supplementary Figures S1-S8.

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Supplementary Methods and Legends - PDF file 94K

Supplemental Figures 1 - 7 PDF 2666K, Supplemental Figure 1. Priming with DC-Tag induces a long-lasting antigenspecific immune response. Supplemental Figure 2. Boosting increases the absolute number of rapidly responding Ag-specific CD8+ splenocytes. Supplemental Figure 3. Boosting does not increase the cytolytic activity of Tagspecific CD8+ T cells. Supplemental Figure 4. Repeated DC-Tag boosting helps maintaining the pool of Ag-specific CD8+ TCM cells. Supplemental Figure 5. Different vaccination schedules do not impact on the pool of Ag-specific CD8+ TCM cells.Supplemental Figure 6. A larger pool of Ag-specific CD8+ TCM cells ensures better protection against tumor challenge. Supplemental Figure 7. Donor-derived CD8+ T cells lead the Tag specific immune response in transplanted TRAMP mice

Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumor-specific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-γ–competent memory CD8+ T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease. Cancer Res; 73(12); 3545–54. ©2013 AACR.

Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra–extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6–6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8+ T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal–regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA–bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell–based cancer treatments. Cancer Res; 72(11); 2746–56. ©2012 AACR.

The bioremediation of waters polluted by Bisphenol A, taken as a model for endocrine disruptors, has been pursued by means of catalytic membranes in bioreactors operating under isothermal and non-isothermal conditions. Laccase from Trametes versicolor was immobilized on nylon membranes grafted with Glycidyl Methacrylate and using Phenylendiamine as spacer. The behaviour of the catalytic membrane was studied as a function of BPA concentration. Affinities of immobilized laccase towards BPA were found to increase with average temperature and under nonisothermal conditions. Percentage increases of enzyme activity, proportional to the applied temperature differences, were found to decrease with the increase of BPA concentrations. Interestingly, the highest levels of BPA biodegradation occurred at the lowest concentrations, in other words those present in wastewaters given the small water solubility of this compound. The results are discussed in terms of the process of thermodialysis by considering the additional BPA fluxes towards the immobilized enzymes driven by the temperature gradients. (c) 2006 Elsevier B.V. All rights reserved.

Background: Cystic Fibrosis (CF)patients with severe disease can have reduced exercise tolerance usually attributed to ventilatory factors and aerobic capacity.Recently,it was shown that Stroke Volume (SV) may be reduced in CF in relation to airways obstruction. Aim of the study: was to evaluate the SV at rest and during exercise in relation to airways obstruction in FC patients compared to control group. Material and methods: We enrolled 20 CF patients,mean age 14.2 ±2.1(range 12-18)divided in two Groups:GrA=FEV1>80% of predicted (n=11);GrB= FEV1 Results: figures 1 and 2 show the mean values of cardiac and respiratory parameters measured. Conclusion: we found lower SV and CO at rest and an attenuated increment of those parameters during exercise in GrB compared to GrA and GrC.Alterated conditions in GrB could be due to higher values of SVR, reduced physical activity and worse nutritional status.

The bioremediation of waters polluted by Bisphenol A, taken as a model for endocrine disruptors, has been pursued by means of catalytic membranes in bioreactors operating under isothermal and non-isothermal conditions. Laccase from Trametes versicolor was immobilized on nylon membranes grafted with Glycidyl Methacrylate and using Phenylendiamine as spacer. The behaviour of the catalytic membrane was studied as a function of BPA concentration. Affinities of immobilized laccase towards BPA were found to increase with average temperature and under nonisothermal conditions. Percentage increases of enzyme activity, proportional to the applied temperature differences, were found to decrease with the increase of BPA concentrations. Interestingly, the highest levels of BPA biodegradation occurred at the lowest concentrations, in other words those present in wastewaters given the small water solubility of this compound. The results are discussed in terms of the process of thermodialysis by considering the additional BPA fluxes towards the immobilized enzymes driven by the temperature gradients.

Using both transplantable and oncogene-driven autochthonous tumor models challenged with dendritic cell-based vaccines, we have recently found that boosting provides a clear advantage in prophylactic settings, unless performed on an excessively tight schedule, which causes the loss of central memory T cells. In therapeutic settings, boosting turned out to be always detrimental.

Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b+Gr1+ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-l-arginine methyl ester (l-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity. Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, l-NAME or sildenafil, and evaluated for CD11b+ cells accumulation in the blood, several organs, and the tumor mass and for disease progression. Results: CD11b+Gr1high, CD11b+Gr1int, and CD11b+Gr1− cells differently accumulated in different organs and especially in the tumor of the two mouse models. l-NAME and sildenafil impaired the immunosuppressive function of CD11b+ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice. Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. Clin Cancer Res; 17(5); 1012–23. ©2011 AACR.

Transplantation of allogeneic hematopoietic stem cells with or without immunocompetent lymphocytes has proved a successful strategy in the treatment of hematological malignancies. We have recently shown that this approach can also cure mouse prostate cancer, provided that it is combined with tumor-specific vaccination. Whether the response to alloantigens acts by providing helper function to enhance vaccine-specific responses or in other ways impinges on vaccine immunogenicity remains to be clarified, and this question is of clinical relevance. In this study, we have addressed this issue by comparing the immunogenicity of dendritic cells pulsed with a peptide derived from a tumor/viral model Ag in recipients of donor cells either syngeneic to the host or differing for either Y-encoded or multiple minor H antigens. We report that vaccination elicits comparable proliferation and differentiation of peptide-specific CD8+ T cells despite concurrent expansion and differentiation of minor H antigen-specific IFN-γ effector T cells. Depletion of alloreactive CD4+ T cells reduced alloreactivity but not vaccine-induced CD8+ T cell priming, suggesting that alloresponses do not provide helper functions in peripheral lymphoid tissues. Vaccine-mediated T cell priming was also preserved in the case of multiple minor H antigen disparities, prone to graft-versus-host disease. Thus, in the context of nonmyeloablative allotransplantation aimed at restoring an effective tumor-specific T cell repertoire, minor H antigen-specific T cells do not interfere with vaccine-induced T cell priming, supporting the notion that posttransplant vaccination is a valuable strategy to boost tumor and pathogen-specific protective immunity.

Consignment implant trays are often an overlooked facet of the supply chain. If not handled properly, they can cost a hospital thousands of dollars in delivery charges as well as potentially decreasing the level of patient safety. It is critical that value analysis committees have input from central service and that time is taken to consider logistics before signing agreements, especially with regard to proper sterilization instructions and delivery method. If trays arrive too late, it is more likely that corners will be cut with the sterilization process.

Using both transplantable and oncogene-driven autochthonous tumor models challenged with dendritic cell-based vaccines, we have recently found that boosting provides a clear advantage in prophylactic settings, unless performed on an excessively tight schedule, which causes the loss of central memory T cells. In therapeutic settings, boosting turned out to be always detrimental.

Purpose. Objectives of this study were to investigate if prostate cancer stem/initiating cells (CSC) obtained from autochthonous tumors possess the molecular characteristics that allow their in vitro and in vivo recognition by cells of the innate and/or adaptive arms of the immune system, and if CSC are source of antigens for the induction of tumor-specific immune responses. Material and Methods. CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were assessed in vitro for the expression of tumor-associated antigens and susceptibility to NK and T cell killing. We also investigated NK and T cells immune surveillance against CSC by measuring the frequency of CSC-induced tumors in immunocompetent and selectively immunodeficient mice. Finally, we assessed if vaccination with dendritic cells pulsed with CSC induced a tumor-specific immune response able to delay the growth of both transplantable and autochthonous prostate tumors. Results. CSC expressed prostate cancer associated antigens, MHC I and MHC II molecules and ligands for natural killer (NK) cells. Indeed, CSC were targets of NK and cytotoxic T lymphocytes both in vitro and in vivo. Vaccination with dendritic cells pulsed with apoptotic CSC induced a tumor-specific immune response that delayed tumor growth in mice challenged with prostate CSC, and caused tumor regression in TRAMP mice. Conclusions. CSC are targets of both innate and adaptive immune responses and could be exploited for the design of novel immunotherapeutic approaches against cancer. Citation Format: Elena Jachetti, Stefania Mazzoleni, Matteo Grioni, Alessia Ricupito, Chiara Brambillasca, Luca Generoso, Arianna Calcinotto, Massimo Freschi, Anna Mondino, Rossella Galli, Matteo Bellone. Prostate cancer stem/initiating cells are targets of both innate and adaptive immunity and elicit potent immune responses against autochthonous prostate tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2613. doi:10.1158/1538-7445.AM2013-2613

A case involving the demineralization of osseous matrix surrounding an intact, necrotic lateral incisor undergoing orthodontic therapy is presented. The treatment involved calcium hydroxide as an interim treatment dressing in conjunction with endodontic therapy. Mechanisms involved in repair are discussed.