PGE2-Induced IDO1 Inhibits the Capacity of Fully Mature DCs to Elicit an In Vitro Antileukemic Immune Response.

In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2

Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

Background: High-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD-1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma. Methods: The human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-γ production, before and after nivolumab exposure, were analyzed. Results: Along with its anti-proliferative and direct pro-apoptotic effect on sarcoma cell lines, sunitinib prompted PD-L1 upregulation on sarcoma cells. Interestingly, sunitinib-treated sarcoma cells drive DCs to full maturation and increase their capacity to induce sarcoma-reactive T cells to produce IFN-γ. Conversely, no effect on T cell proliferation and T cell subpopulation composition was observed. Moreover, both bone and synovial sarcoma cell lines induced Tregs through DCs but sunitinib treatment completely abrogated Treg induction. Finally, sarcoma cell lines induced PD-1 upregulation on both effector T cells and Tregs when loaded into DCs, providing a rationale for using PD-1 blockade. Indeed, PD-1 blockade by nivolumab synergized with sunitinib in inducing IFN-γ-producing effector T cells. Conclusions: Taken together, our in vitro data indicate that the treatment of sarcoma cells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers. DC-targeted drugs, including toll-like receptor 3 inhibitors and CD47 inhibitors, are under development and our preclinical model might help to better design their clinical application

The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells.

Dendritic cells (DCs) are professional APCs that have a role in the initiation of adaptive immune responses and tolerance. Among the tolerogenic mechanisms, the expression of the enzyme IDO1 represents an effective tool to generate T regulatory cells. In humans, different DC subsets express IDO1, but less is known about the IDO1-related enzyme IDO2. In this study, we found a different pattern of expression and regulation between IDO1 and IDO2 in human circulating DCs. At the protein level, IDO1 is expressed only in circulating myeloid DCs (mDCs) and is modulated by PGE2, whereas IDO2 is expressed in both mDCs and plasmacytoid DCs and is not modulated by PGE2. In healthy subjects, IDO1 expression requires the presence of PGE2 and needs continuous transcription and translation, whereas IDO2 expression is constitutive, independent from suppressor of cytokine signaling 3 activity. Conversely, in patients suffering from inflammatory arthritis, circulating DCs express both IDO1 and IDO2. At the functional level, both mDCs and plasmacytoid DCs generate T regulatory cells through an IDO1/IDO2-dependent mechanism. We conclude that, in humans, whereas IDO1 provides an additional mechanism of tolerance induced by proinflammatory mediators, IDO2 is stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DCs

Association between Mediterranean lifestyle and perception of well-being and distress in a sample population of university Italian students

We investigated the extent to which adherence to the Mediterranean diet (MD) in combination with Mediterranean lifestyle factors influenced students’ perceptions of subjective well-being (SWB) and distress. 939 undergraduates completed a survey to assess sociodemographic and lifestyle characteristics, including adherence to the MD, depression, anxiety, stress, and SWB. Data were analysed with correlation, logistic, and multiple linear regression models. Higher adherence to MD correlated with better SWB. Fruit, red meat, sweet and caffeinated beverages contributed significantly. However, it was the combination of adherence to MD with other factors, including quality of social relationships, income, smoking, sleep, and physical activity that better predicted SWB. Our results confirm the positive influence of MD on SWB. However, they also suggest the need to consider perceptions of well-being by a more holistic approach that considers physical and social factors simultaneously to improve the development of more effective educational and motivational programmes.info:eu-repo/semantics/publishedVersio

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth

The association between maternal resolution of the diagnosis of autism, maternal mental representations of the relationship with the child, and children's attachment

Mothers who were classified as resolved showed higher levels of secure base, own and other perspective-taking, and lower level of neutralization than mothers classified as unresolved. Mothers with a higher level of neu- tralization, compared with mothers with a lower level of neutralization, had children with a higher level of avoidance. The study analyzed the associations between the maternal resolution state of mind of the child\u2019s diagnosis, maternal mental representations of the relation with the child, and children\u2019s attachment. The associations made between the maternal resolution state of mind and some mothers\u2019 and children\u2019s variables were also analyzed. The participants were 21 children with high functioning autism or Asperger syndrome (Mage = 7 years 9 months; SD = 2 years 4 months) and their mothers (Mage = 41 years 2 months; SD = 4 years 7 months). Maternal resolution status was associated with the type of diagnosis and mothers\u2019 age. Mothers who were classified as \u2018resolved\u2019, showed higher levels of secure base, their own and other perspective-taking, and a lower level of neutralization, than mothers classified as \u2018unresolved\u2019. Mothers with a higher level of neutralization, compared with mothers with a lower level of neutralization, had children with a higher level of avoidance

Flow cytometry T cell profiling in a recent-onset narcoleptic type 1 child: a case report

Background: Recent studies have disclosed the involvement of T cells in narcolepsy type 1 pathogenesis. We characterized the T cell subsets distribution in a recent-onset child at two different time points, two months from disease onset (T0) and 10 months later (follow-up), respectively. Methods: Peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) lymphocytes were characterized by flow cytometry at both evaluations. The distribution of T cell subsets was compared between the two time points, and the fold change was calculated as the CSF/PBMC frequencies ratio. Results: The patient showed a 2-fold increase in the frequency of CD4+ EMRA T cells, and an increase of more than one and a half in the frequency of CD4+ CM T cells in CSF at follow-up compared to T0. Moreover, the distribution of CD4+ EM T cells was slightly increased at T0 compared to follow-up. In PBMCs, the CD4+ and CD8+ T cell subsets showed a slight decrease in CM cells at the follow-up. Finally, the CSF/PBMC fold-change ratio showed a 3-fold increase of CD4+ and CD8+ CM T cells at the follow-up, a rise up to 1.5-fold of CD4+ EMRA subsets and a slight decrease in CD4+ EM T cells. Conclusions: Our data suggest that variations in the frequency of EM vs. CM of CD4+ and CD8+ T cell subsets in the CSF and in the CSF/PBMC fold change may represent a biological marker of disease progression

Flow cytometry T cell profiling in a recent-onset narcoleptic type 1 child: a case report

Background: Recent studies have disclosed the involvement of T cells in narcolepsy type 1 pathogenesis. We characterized the T cell subsets distribution in a recent-onset child at two different time points, two months from disease onset (T0) and 10 months later (follow-up), respectively. Methods: Peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) lymphocytes were characterized by flow cytometry at both evaluations. The distribution of T cell subsets was compared between the two time points, and the fold change was calculated as the CSF/PBMC frequencies ratio. Results: The patient showed a 2-fold increase in the frequency of CD4+ EMRA T cells, and an increase of more than one and a half in the frequency of CD4+ CM T cells in CSF at follow-up compared to T0. Moreover, the distribution of CD4+ EM T cells was slightly increased at T0 compared to follow-up. In PBMCs, the CD4+ and CD8+ T cell subsets showed a slight decrease in CM cells at the follow-up. Finally, the CSF/PBMC fold-change ratio showed a 3-fold increase of CD4+ and CD8+ CM T cells at the follow-up, a rise up to 1.5-fold of CD4+ EMRA subsets and a slight decrease in CD4+ EM T cells. Conclusions: Our data suggest that variations in the frequency of EM vs. CM of CD4+ and CD8+ T cell subsets in the CSF and in the CSF/PBMC fold change may represent a biological marker of disease progression