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Cancer vaccines can be utilized in combination with checkpoint inhibitors to optimally stimulate the anti -tumor immune response. Uptake of vaccine antigen by antigen presenting cells (APCs) is a prerequisite for T cell priming, but often relies on non-specific mechanisms. Here, we have developed a novel vaccination strategy consisting of cancer antigen -containing liposomes conjugated with CD169- or DC -SIGN -specific nanobodies (single domain antibodies) to achieve specific uptake by APCs. Our studies demonstrate efficient nanobody liposome uptake by human and murine CD169 + and DC -SIGN + APCs in vitro and in vivo when compared to control liposomes or liposomes with natural ligands for CD169 and DC -SIGN. Uptake of CD169 nanobody liposomes resulted in increased T cell activation by human APCs and stimulated naive T cell priming in mouse models. In conclusion, while nanobody liposomes have previously been utilized to direct drugs to tumors, here we show that nanobody liposomes can be applied as vaccination strategy that can be extended to other receptors on APCs in order to elicit a potent immune response against tumor antigens.

Studies on the framing of the refugee crisis have focused on media and political discourses, revealing contrasting views and an increasing politicization of immigration. However, the framing-of-asylum discourse in relation to the reception and settlement of asylum seekers in local communities has so far received less attention, especially when conflictual dynamics emerge. This article investigates the ways in which experts at different levels make sense of how the refugee crisis has unfolded in local communities in Italy. Insofar as asylum governance has become a contentious issue, it looks at conflictual situations. The research challenges the binary between humanitarian and fear frames by suggesting the prevalence of a managerialist frame focusing on a problematic implementation of asylum policies. Taking into consideration the opinions of local experts, it also reveals a shift from a fear frame to an inconvenience frame, which denies xenophobic discourses on invasion or social/public disorder in local communities, but finds other reasons to deny acceptance. The article also adds to the study of the horizontal dynamics between public and private actors, which are central, especially at the local level, and introduces refugees as subjects who actively participate in the “battleground” of asylum governance. Therefore, claims about a negotiated order between different tiers of governance within the multilevel governance approach are challenged.

This article comparatively examines forms of (im)mobility among refugees and asylum seekers (RAS) in coping with dispersal process, restrictive migration policies and local socio-economic characteristics in three cities of Northern Italy. Drawing on qualitative data, it sheds light on the everyday forms of (im)mobility of RAS to resist structural barriers limiting their opportunities to access jobs and welfare services. The Results show that people's capacity to overcome barriers depends upon individual characteristics and informal networks, and is shaped by particularities of local contexts. While people's regular legal status is considered an important resource in achieving goals, refugees and holders of international protection often have to adopt (im)mobility practices to access resources in contexts that do not facilitate their integration. This article highlights the inefficiency of integration and reception policies and advances the theoretical debate on the link between being (im)mobile and agency by calling authors to pay more attention to the (in)voluntary nature of spatial (im)mobility. Finally, it shows the ambivalent outcome of (im)mobilities in terms of agency, highlighting the implications for individuals before and during the COVID-19 pandemic.

Il saggio affronta il tema della «rifugiatizzazione» dei senza dimora a partire da un contesto di particolare interesse: la città di Como, un luogo di confine dove la presenza di rifugiati, soprattutto se senza dimora, ha catalizzato le paure dei cittadini e delle Istituzioni pubbliche. A fronte di un’avversione diffusa, una parte della società civile si è invece mobilitata per fornire aiuto e supporto ai più bisognosi. Il saggio prende quindi in esame l’evoluzione di uno specifico campo di azione solidale che si è progressivamente (ri)strutturato in città a fronte di ripetuti momenti di «crisi» occorsi tra il 2016 e la Pandemia da Covid-19. Adottando una prospettiva analitica diacronica, sono individuate le strategie che gli attori del terzo settore hanno ideato e poi introdotto per rispondere ad una serie di necessità non coperte dal mercato e dalle politiche di welfare formali. Da questo punto di vista, la presenza di «rifugiati senza dimora» rappresenta tanto un fattore di sfida e di stress istituzionale ed organizzativo, quanto una spinta per l’innovazione nei percorsi solidali che l’azione umanitaria può apportare su un tema socialmente e politicamente sensibile.

This article elaborates on the activities developed by various actors from the civil society in favour of non-deported refused asylum seekers (NDRAS) through the lens of 'de-bordering solidarity'. Drawing on qualitative data collected in two small Italian cities ruled by anti-immigrant coalitions, this study explores the rationales and outcomes of migrant supporters' actions in providing help to NDRAS, thus deepening the action of pro-immigrant civil society in small urban centres. The findings show that, while civil society's engagement in the provision of basic needs to vulnerable people is unconditional, legal advice and practical help for access to regular status can be more selective and reflect lack of human and financial resources available, the low probability of a part of NDRAS to achieve legal status, low demand in local labour markets, and social workers' and volunteers' subjectivities. Despite recognizing such limits in solidarity activities, this article shows that civil society in practice challenges deportation policies through practical and daily solidarity that assumes political and cultural meanings. Based on these findings, this article suggests durable solutions for addressing the issues connected with the presence of NDRAS.

Background Acid–base status in full-term pregnant women is characterised by hypocapnic alkalosis. Whether this respiratory alkalosis is primary or consequent to changes in CSF electrolytes is not clear. Methods We enrolled third-trimester pregnant women (pregnant group) and healthy, non-pregnant women of childbearing age (controls) undergoing spinal anaesthesia for Caesarean delivery and elective surgery, respectively. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (), and pH were measured in simultaneously collected CSF and arterial blood samples. Results All pregnant women (20) were hypocapnic, whilst only four (30%) of the controls (13) had an arterial <4.7 kPa (P<0.001). The incidence of hypocapnic alkalosis was higher in the pregnant group (65% vs 8%; P=0.001). The CSF-to-plasma Pco2 difference was significantly higher in pregnant women (1.5 [0.3] vs 1.0 [0.4] kPa; P<0.001), mainly because of a decrease in arterial Pco2 (3.9 [0.3] vs 4.9 [0.5] kPa; P<0.001). Similarly, the CSF-to-plasma difference in SID was less negative in pregnant women (–7.8 [1.4] vs –11.4 [2.3] mM; P<0.001), mainly because of a decreased arterial SID (31.5 [1.2] vs 36.1 [1.9] mM; P<0.001). The major determinant of the reduced plasma SID of pregnant women was a relative increase in plasma chloride compared with sodium. Conclusions Primary hypocapnic alkalosis characterises third-trimester pregnant women leading to chronic acid–base adaptations of CSF and plasma. The compensatory SID reduction, mainly sustained by an increase in chloride concentration, is more pronounced in plasma than in CSF, as the decrease in Pco2 is more marked in this compartment.

Background Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs. Methods We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset. Results The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement. Conclusions Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastas

Cancer vaccines aim to efficiently prime cytotoxic CD8+ T cell responses which can be achieved by vaccine targeting to dendritic cells. CD169+ macrophages have been shown to transfer antigen to dendritic cells and could act as an alternative target for cancer vaccines. Here, we evaluated liposomes containing the CD169/Siglec-1 binding ligand, ganglioside GM3, and the non-binding ligand, ganglioside GM1, for their capacity to target antigens to CD169+ macrophages and to induce immune responses. CD169+ macrophages demonstrated specific uptake of GM3 liposomes in vitro and in vivo that was dependent on a functional CD169 receptor. Robust antigen-specific CD8+ and CD4+ T and B cell responses were observed upon intravenous administration of GM3 liposomes containing the model antigen ovalbumin in the presence of adjuvant. Immunization of B16-OVA tumor bearing mice with all liposomes resulted in delayed tumor growth and improved survival. The absence of CD169+ macrophages, functional CD169 molecules, and cross-presenting Batf3-dependent dendritic cells (cDC1s) significantly impaired CD8+ T cell responses, while B cell responses were less affected. In conclusion, we demonstrate that inclusion of GM3 in liposomes enhance immune responses and that splenic CD169+ macrophages and cDC1s are required for induction of CD8+ T cell immunity after liposomal vaccination.

The multi-level governance (MLG) approach is widely used to understand the complex processes of immigration policymaking. In this literature review, we consider both (i) the vertical dimension of MLG: the local, regional, national, European, or even global level; and (ii) the horizontal dimension of MLG: the relations between public and non-public actors. While focusing on the local level, this review identifies a trend regarding, on the one hand, local processes of bordering, and local policies of inclusion on the other. Furthermore, the article reviews how civil society has responded to the arrival of refugees. It identifies how this literature pays insufficient attention to dimensions of conflict and, more specifically, to how local borders can be challenged. Moreover, it shows a lack of attention to anti-migrant responses, and to the interaction between migrants and civil society regarding immigration governance. Concluding, the paper argues for the adoption of a “battleground” perspective as a more dynamic basis for the MLG approach., L’approche théorique de la gouvernance multi-niveaux (GMN) est largement utilisée pour comprendre les processus complexes d’élaboration des politiques migratoires. Dans cet article, nous proposons, sous la forme d’un état de l’art, une analyse de la dimension verticale (niveau local, régional, national, européen ou mondial) et horizontale (relations entre acteurs publics et non publics) de la GMN. Centré sur le niveau local et sur les questions d’asile, cet article identifie une tendance concernant, d’une part, les processus locaux de définition des frontières, et d’autre part, les politiques locales d’inclusion. En outre, nous examinons comment la société civile a réagi face aux arrivées de réfugiés. L’article montre que la littérature sur la GMN n’a pas accordé assez d’attention à la question du conflit et à la façon dont celui-ci peut déplacer les frontières sociales au niveau local. La littérature a insuffisamment abordé les mobilisations anti-migrants et les interactions entre migrants et société civile. En conclusion, nous ajoutons que le concept de « champ de bataille » (Battlegrounds) permet une compréhension plus dynamique de la GMN., La gobernanza multinivel (MLG por su acrónimo inglés) es un enfoque ampliamente utilizado para comprender los complejos procesos de formulación de políticas públicas en torno al tema de la inmigración. Esta revisión de la literatura analiza tanto la dimensión vertical de la MLG: el nivel local, regional, nacional, europeo o incluso global; como la dimensión horizontal de la misma: las relaciones entre actores públicos y no públicos. Centrándose en el nivel local y particularmente en el tema del asilo, esta revisión bibliográfica identifica una tendencia con respecto a los procesos locales de frontera por un lado, y las políticas locales de inclusión por el otro. Las dimensiones del conflicto y el cómo se desafían las fronteras locales no se tratan exhaustivamente en este documento. Sin embargo, a este respecto revisamos cómo la sociedad civil ha respondido a la llegada de refugiados. Esta literatura no ha otorgado suficiente atención a las respuestas anti-inmigrantes, y a cómo la sociedad civil y los migrantes interactúan en relación a la gobernanza de la inmigración. Concluimos elaborando sobre la manera en la que un marco conceptual en términos de «campo de batalla» (Battlegrounds) permite aplicar una perspectiva dinámica al entendimiento de la gobernanza multinivel o MLG.

Injection of antigenic peptides has been widely used as a vaccine strategy to boost T cell immunity. However, the poor immunogenicity of single peptides can potentially be strengthened through modification of the tertiary structure and the selection of the accompanying adjuvant. Here, we generated antigenic peptides into non-linear trimers by solid phase peptide synthesis, thereby enhancing antigen presentation by dendritic cells to CD8+ T cells in vitro and in vivo. CD8+ T cells from mice vaccinated with trimers showed an KLRG1+ effector phenotype and were able to recognize and kill antigen-expressing tumor cells ex vivo. Importantly, trimers outperformed synthetic long peptide in terms of T cell response even when equal number of epitopes were used for immunization. To improve the synthesis of trimers containing difficult peptide sequences, we developed a novel small molecule that functions as conjugation platform for synthetic long peptides. This platform, termed Antigen MAtriX (AMAX) improved yield, purity and solubility of trimers over conventional solid phase synthesis strategies. AMAX outperformed synthetic long peptides in terms of both CD8+ and CD4+ T cell responses and allowed functionalization with DC-SIGN-binding carbohydrates for in vivo dendritic cell targeting strategies, boosting T cell responses even further. Moreover, we show that ago

Contains fulltext : 215800.pdf (publisher's version ) (Open Access), Glioblastoma is the most prevalent and aggressive primary brain tumour for which total tumour lysate-pulsed dendritic cell vaccination is currently under clinical evaluation. Glioblastoma extracellular vesicles (EVs) may represent an enriched cell-free source of tumour-associated (neo-) antigens to pulse dendritic cells (DCs) for the initiation of an anti-tumour immune response. Capture and uptake of EVs by DCs could occur in a receptor-mediated and presumably glycan-dependent way, yet the glycan composition of glioblastoma EVs is unknown. Here, we set out to characterize the glycocalyx composition of glioblastoma EVs by lectin-binding ELISA and comprehensive immunogold transmission electron microscopy (immuno-TEM). The surface glycan profile of human glioblastoma cell line-derived EVs (50-200 nm) was dominated by alpha-2,3- and alpha-2,6 linked sialic acid-capped complex N-glycans and bi-antennary N-glycans. Since sialic acids can trigger immune inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, we screened for Siglec ligands on the EVs. Glioblastoma EVs showed significant binding to Siglec-9, which is highly expressed on DCs. Surprisingly, however, glioblastoma EVs lack glycans that could bind Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, CD209), a receptor that mediates uptake and induction of CD4(+) and CD8(+) T cell activation. Therefore, we explored whether modification of the EV glycan surface could reduce immune inhibitory Siglec binding, while enhancing EV internalization by DCs in a DC-SIGN dependent manner. Desialylation with a pan-sialic acid hydrolase led to reduction of sialic acid expression on EVs. Moreover, insertion of a high-affinity ligand (Lewis(Y)) for DC-SIGN resulted in a four-fold increase of uptake by monocyte-derived DCs. In conclusion, we show that the glycocalyx composition of EVs is a key factor of efficient DC targeting and that modification of the EV glycocalyx potentiates EVs

Contains fulltext : 215802.pdf (publisher's version ) (Open Access), The human skin is an attractive anti-tumor vaccination site due to the vast network of dendritic cell (DC) subsets that carry antigens to the draining lymph nodes and stimulate tumor specific CD4(+) and CD8(+) T cells in. Specific vaccine delivery to skin DC can be accomplished by targeting glycan coated antigens to C-type lectin receptors (CLRs) such as DC-SIGN expressed by human dermal DCs and Langerin expressed by Langerhans cells (LCs), which facilitate endocytosis and processing for antigen presentation and T cell activation. Although there are multiple human skin DC subsets, targeting individual DC subsets and receptors has been a focus in the past. However, the simultaneous targeting of multiple human skin DC subsets that mobilize the majority of the skin antigen presenting cells (APC) is preferred to accomplish more robust and efficient T cell stimulation. Dual CLR targeting using a single tumor vaccine has been difficult, as we previously showed Langerin to favor binding and uptake of monovalent glyco-peptides whereas DC-SIGN favors binding of larger multivalent glyco-particles such as glyco-liposomes. Methods: We used branched polyamidoamine (PAMAM) dendrimers as scaffold for melanoma specific gp100 synthetic long peptides and the common DC-SIGN and Langerin ligand Lewis Y (Le(Y)), to create multivalent glyco-dendrimers with varying molecular weights for investigating dual DC-SIGN and Langerin targeting. Using DC-SIGN(+) monocyte derived DC (moDC) and Langerin(+) primary LC we investigated glyco-dendrimer CLR targeting properties and subsequent gp100 specific CD8(+) T cell activation in vitro. In situ targeting ability to human dermal DC and LC through intradermal injection in a human skin explant model was elucidated. Results: Dual DC-SIGN and Langerin binding was achieved using glyco-dendrimers of approximately 100kD, thereby fulfilling our criteria to simultaneously target LCs and CD1a(+) and CD14(+) dermal DC in situ. Both DC-SIGN and Langerin targetin

Il contributo analizza le pratiche attive in Italia per accompagnare la transizione alla maggiore età dei minori stranieri non accompagnati. Il tema è di particolare rilievo, in quanto il 60% dei msna presenti in Italia ha 17 anni e dunque ha la necessità di acquisire competenze e abilità per inserirsi nel mondo nel lavoro, per trovare casa e peri la gestione della vita autonoma.