Uso de recursos hídricos en las actividades productivas del Municipio de General Pueyrredon, Buenos Aires

El agua es un recurso natural renovable, escaso y crítico para el desarrollo de la vida, por lo que también resulta estratégico. La disponibilidad natural de agua por habitante ha disminuido globalmente en un 30% en las últimas dos décadas debido al impacto del crecimiento poblacional, el cambio climático y el desarrollo económico (FAO, 2020). Dado este escenario y de acuerdo a la Agenda 2030 de la ONU, la consecución de diversos Objetivos de Desarrollo Sostenible demanda una urgente definición de esquemas de gestión sostenibles y equitativos para el uso y consumo del agua (ONU, 2018).Fil: Anrriquez Anlauf, Dulce Serena. Universidad Nacional de Mar del Plata. Facultad de Ciencias Económicas y Sociales; Argentina.Fil: Lacaze, María Victoria. Universidad Nacional de Mar del Plata. Facultad de Ciencias Económicas y Sociales; Argentina.Fil: Zilio, Mariana I. CONICET. Universidad Nacional del Sur. Departamento de Economía; Argentina

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We\ua0found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T\ua0cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy

Role of Arginase 1 and Nitric Oxide Synthase 2 as enzymatic mediators of the immunosuppressive activity in tumor-infiltrating myeloid derived suppressor cells

MDSCs (myeloid derived suppressor cells) are one of the most important immunoregulatory populations involved in the generation of a permissive environment allowing tumor escape, progression and spreading. In physiologic conditions MDSCs protect the organism from exacerbated immune responses in order to protect surrounding tissues from damage. During tumor growth, cancer cells produce TDSFs (tumor derived soluble factors), which induce MDSC accumulation and their acquisition of a persistent suppressive activity. Among the several mechanisms exploited by MDSCs to exert their suppressive function, L-arginine metabolism seems to be fundamental for the alteration of the tumor microenvironment and for the generation of T effector cell dysfunctions. This work highlights the in vivo requirement for ARG1 and NOS2 in the biology of MDSCs during tumor development. MDSCs are known for their phenotypic and functional complexity. It is clear that many factors can shape their identity and function: here we show, indeed that tumor microenvironment can “educate” them progressively. We illustrate that ARG1 and NOS2 are fundamental for MDSC-mediated T cell suppression in vivo but also for the expansion of the suppressive subsets of MDSCs. L-arginine metabolism mediated by these enzymes is crucial for tumor spreading and metastasis, as depletion of either enzyme produces a 50-75% reduction in the number of lung metastases. Finally, we show that the effects mediated by the novel drug AT38 are mediated by ARG1/NOS2 reduction and sufficient to improve ACT (adoptive cell therapy) therapeutic approaches. Data here produced represent a body of evidence that could be exploited for improving the efficiency of anti-cancer therapies, and identifies ARG1 and NOS2 as key targets for restoring T cell mediated tumor responses.Le MDSC rappresentano un’importante popolazione immunoregolatoria coinvolta nella generazione di un microambiente tumorale permissivo, in grado di favorire l’instaurarsi, la crescita e la diffusione del tumore. Le MDSC sono fisiologicamente presenti nell’organismo dove, in caso di infezione o infiammazione si espandono transitoriamente allo scopo di limitare risposte immunitarie eccessive e quindi di evitare danni ai tessuti. Durante la crescita del tumore, le cellule tumorali secernono fattori solubili in grado di indurre l’accumulo delle MDSC e l’acquisizione del loro fenotipo soppressivo. Tra i diversi meccanismi utilizzati dalle MDSC per svolgere le loro funzioni, il metabolismo dell’aminoacido L-arginina sembra avere un ruolo fondamentale nell’alterazione del microambiente tumorale e nella generazione di linfociti T effettori incapaci di generare un’adeguata risposta anti-tumorale. In questo lavoro è stato studiato il coinvolgimento degli enzimi ARG1 e NOS2 nell’attività delle MDSC durante lo sviluppo tumorale. Le MDSC sono note per la loro complessità sia fenotipica che funzionale ed ormai è chiaro che queste caratteristiche possono essere plasmate da molti stimoli differenti. In questo lavoro, infatti, è stato dimostrato che durante la sua crescita il tumore è in grado di “educare” le MDSC. Abbiamo inoltre mostrato che ARG1 e NOS2 sono fondamentali non solo per la soppressione in vivo dei linfociti T ma anche per l’ espansione delle MDSC. Risulta inoltre evidente come il metabolismo di L-arginina mediato da ARG1 e NOS2 sia cruciale nella per la diffusione delle cellule tumorali e per il processo metastatico. Infatti la deplezione di anche uno solo di questi due enzimi provoca una riduzione del 50-75% nel numero di metastasi polmonari. Infine, abbiamo dimostrato come l’effetto mediato da un nuovo farmaco, AT38, sia dovuto, almeno in parte, alla riduzione di ARG1 e NOS2 e come questo sia sufficiente a migliorare l’efficacia di approcci terapeutici, quali il trasferimento adottivo. I dati riportati in questa tesi rappresentano quindi una solida evidenza del fatto che ARG1 e NOS2 possano rappresentare un rilevante bersaglio terapeutico in grado di aumentare l’efficacia delle terapie anti-tumorali

Neutrophils and Granulocytic MDSC: The Janus God of Cancer Immunotherapy

Neutrophils are the most abundant circulating blood cell type in humans, and are the first white blood cells recruited at the inflammation site where they orchestrate the initial immune response. Although their presence at the tumor site was recognized in the 1970s, until recently these cells have been neglected and considered to play just a neutral role in tumor progression. Indeed, in recent years neutrophils have been recognized to play a dual role in tumor development by either assisting the growth, angiogenesis, invasion, and metastasis or by exerting tumoricidal action directly via the secretion of antitumoral compounds, or indirectly via the orchestration of antitumor immunity. Understanding the biology of these cells and influencing their polarization in the tumor micro- and macro-environment may be the key for the development of new therapeutic strategies, which may finally hold the promise of an effective immunotherapy for cancer

Neutrophils and Granulocytic MDSC: The Janus God of Cancer Immunotherapy

Neutrophils are the most abundant circulating blood cell type in humans, and are the first white blood cells recruited at the inflammation site where they orchestrate the initial immune response. Although their presence at the tumor site was recognized in the 1970s, until recently these cells have been neglected and considered to play just a neutral role in tumor progression. Indeed, in recent years neutrophils have been recognized to play a dual role in tumor development by either assisting the growth, angiogenesis, invasion, and metastasis or by exerting tumoricidal action directly via the secretion of antitumoral compounds, or indirectly via the orchestration of antitumor immunity. Understanding the biology of these cells and influencing their polarization in the tumor micro- and macro-environment may be the key for the development of new therapeutic strategies, which may finally hold the promise of an effective immunotherapy for cancer

CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor

BackgroundCancer-induced ‘emergency’ myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets.MethodsWe used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6G+cells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5.Results4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer.ConclusionsOur data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages

NANOPARTICLE CONJUGATES AND USES THEREOF

Described herein are nanoparticle-based compositions, kits and methods and platforms for delivering one or more nucleic acids to a cell