Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy

Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis. Treatment at diagnosis has limited efficacy and there is no standardised treatment at recurrence. New, personalised treatment options are under investigation, although challenges persist for heterogenous tumours such as GBM. Gene editing technologies are a game changer, enabling design of novel molecular-immunological treatments to be used in combination with chemoradiation, to achieve long lasting survival benefits for patients. Here, we review the literature on how cutting-edge molecular gene editing technologies can be applied to known and emerging tumour-associated antigens to enhance chimeric antigen receptor T and NK cell therapies for GBM. A tight balance of limiting neurotoxicity, avoiding tumour antigen loss and therapy resistance, while simultaneously promoting long-term persistence of the adoptively transferred cells must be maintained to significantly improve patient survival. We discuss the opportunities and challenges posed by the brain contexture to the administration of the treatments and achieving sustained clinical responses.publishedVersio

Therapeutic potential and challenges of natural killer cells in treatment of solid tumors

Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.publishedVersio

Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma

Glioblastoma is a deadly brain cancer with limited treatment options. Targeting chondroitin sulfate proteoglycan 4 (CSPG4, best known as NG2) with the monoclonal antibody mAb9.2.27 and activated natural killer (NK) cells abrogated the tumor growth and prolonged the survival of glioblastoma-bearing animals by favoring the establishment of a pro-inflammatory microenvironment. The combination of NK cells and mAb9.2.27 recruited ED1+CCR2low macrophages that stimulated ED1+ED2lowMHCIIhigh microglial cells to exert robust cytotoxicity. Our findings demonstrate the therapeutic potential of targeting salient tumor associated-antigens.publishedVersio

Origen de las dolomías en la zona de Riópar (SE España): implicaciones sobre la geología de la Zona Prebética

In the present study a petrographic description and C-O stable isotope data of dolostone occurrences at the Riópar area (Mesozoic Prebetic Zone) are presented. Results constrain the origin and dolomitization processes for each dolomitic unit providing new insights on the geology of the Prebetic. Dolostones are grouped in: i) large seismicscale stratabound dolostones hosted in limestones of Lower Jurassic, Middle Jurassic and Upper Cretaceous ages; and ii) stratabound and patchy dolostones hosted in a carbonatic sequence of Upper Jurassic to Lower Cretaceous age. Two dolomitizing origins have been distinguished: i) a low-temperature dolomitization originated from seawater (seismicscale stratabound dolomitized limestones); ii) a hydrothermal dolomitization originated by high temperature brines (stratabound and patchy dolomitized limestones). Results of this study can be used as a guide for other poorly known dolomitic areas in the Prebetic Zone.En este estudio se presenta la descripción petrográfica y los datos isotópicos de C y O de distintos cuerpos de dolomías en la zona de Riópar (Zona Mesozoica del Prebético). Los resultados obtenidos permiten acotar el origen de cada miembro dolomítico, aportando nuevos datos geológicos en el Prebético. Dichos cuerpos se agrupan en: i) dolomías estratiformes de gran extensión hospedadas en calizas del Jurásico Inferior y Medio, así como del Cretácico Superior; ii) dolomías de tipo estratiforme y en forma de parches hospedadas en una secuencia carbonatada del Jurásico Superior al Cretácico inferior. El origen de estas dolomitizaciones se atribuye a: i) interacción con agua marina presumiblemente a baja temperatura (dolomías estratiformes de gran extensión); ii) presencia de salmueras hidrotermales de alta temperatura (dolomías estratiformes y parcheadas). Estos resultados pueden servir de guía para otras áreas dolomitizadas poco estudiadas en la zona del Prebético.Depto. de Mineralogía y PetrologíaFac. de Ciencias GeológicasTRUEMinisterio de Economía y Competitividad (MINECO)pu

C and O isotopes of the Riópar Non-Sulfide Zn Ores (Albacete, SE Spain)

Depto. de Mineralogía y PetrologíaFac. de Ciencias GeológicasFALSEEspaña. Ministerio de Economía y Competitividadpu

The building stone of the Roman city of Lixus (NW Morocco) : provenance, petrography and petrophysical characterization

Characterization of building material is a key tool to assess deterioration processes and improve potential restoration works of archaeological sites. The aim of this paper is to identify and characterize the building stone used in the construction of the Phoenician-Roman city of Lixus (Larache, Morocco) by means of petrographic and petrophysical technics. Based on the visual analysis of the monuments, three major building stones (i.e., lithotypes) have been identified: (1) Oligocene sandstones, (2) Quaternary sandstones, and (3) Quaternary conglomerates. Based on the analysis of the regional geology and exploitation marks, these three lithotypes have been identified to crop out in the surroundings of Lixus and the quarries, presumably Roman in origin, recognized. The Oligocene sandstone is the primary building stone in Lixus as form and crop out extensively in the Tchemmis hill, at top of which the city is settled. The Quaternary sandstones and conglomerates, which represent nearshore deposits and eolianites, are less abundant as building rocks in Lixus and crop out along the Atlantic coast where form part pf the cliffs close to Larache. Petrographic results indicate that lithotypes differ notably in grain size, ratio of detrital to allochemical components, and the configuration of their porous system. Mechanical analysis show that the Oligocene sandstones are more resistant to compression than the Quaternary sandstones and conglomerates, the latter exhibiting low compressive strength. The Oligocene sandstones, which display scarce porosity and permeability, show a hydric behaviour characterized by a very low degree of absorbing and desorbing water, likely resulting from a poor connectivity of the pore network. Contrary to later lithotype, the Quaternary sandstones and conglomerates, which exhibit very high porosity and permeability, display a hydric behaviour characterized by high degree of both absorbing and desorbing water. This behaviour is attributed to both the low degree of cementation and excellent connectivity of the porous network of the lithotype typical of coastal deposists. Finally, the accelerated artificial aging test they do not show a significant weight loss after twelve cycles of salt crystallization, indicating that the three lithotypes are not vulnerable to sodium sulphate attacks. Results of this study indicate that the good state of conservation of the building rocks of Lixus is linked to intrinsic factors as mineralogy and petrophysical characteristics together with the favourable effect of the climatic condition of the study area

Petrography and geochemistry of fault-controlled hydrothermal dolomites in the Riópar area (Prebetic Zone, SE Spain)

The present paper reports the first detailed petrographical and geochemical studies of hydrothermal dolomites related to MVT Zn-(Fe-Pb) deposits in the Riópar area (Mesozoic Prebetic Basin, SE Spain), constraining the nature, origin and evolution of dolomitizing and ore-forming fluids. Mapping and stratigraphic studies revealed two stratabound dolostone geobodies connected by other patchy bodies, which replace carbonate units of Upper Jurassic to Lower Cretaceous ages. These dolostones are associated to the W-E trending San Jorge fault, indicating a main tectonic control for fluid flow. Seven different dolomite types were identified: i) matrix-replacive planar-s (ReD-I); ii) matrix-replacive planar-e (ReD-II); iii) planar-e sucrosic cement (SuD); iv) non-planar grey saddle dolomite cement (SaD-I) pre-dating Zn-(Fe-Pb) sulfides; v) non-planar milky to pinkish saddle dolomite cement (SaD-II) post-dating Zn-(Fe-Pb) ores; vi) ore-replacive planar-e porphyrotopic (PoD); and vii) planar-s cloudy cement (CeD). Meteoric calcite types were also recognized. The different dolomite types are isotopically characterized by: i) depleted δ18O (from +25.1 to +27.6¿ V-SMOW) and δ13C (from -2.3 to +0.9¿ V-PDB) values compared to Upper Jurassic to Lower Cretaceous limestone signature (δ18O: +27.6 to +30.9¿ V-SMOW; δ13C: +0.5 to +3.2¿ V-PDB); and ii) 87Sr/86Sr ratios for the main dolomitization phases (ReD and SuD: 0.70736-0.70773) close to the Jurassic and Cretaceous carbonate values (0.70723-0.70731) whereas more radiogenic values (0.70741-0.70830) for saddle dolomites (SaD) related to the Zn-(Fe-Pb) sulfide mineralization prevailed after fluid interaction with Rb-bearing minerals. Microthermometrical studies on two-phase liquid and vapor fluid inclusion populations in planar and non-planar dolomites and sphalerite show homogenization temperatures between 150 and 250ºC. These data indicate that both planar and non-planar dolomite textures formed at high-temperatures under hydrothermal conditions in deep-burial diagenetic environments. The main dolomitizing phase (ReD-I/ReD-II and SaD-I) shows low to moderate fluid inclusions salinity (5 to 14 wt.% eq. NaCl), whereas the dolomitization related to ore precipitation (sphalerite and SaD-II) spreads to higher salinity values (5 to 25 wt.% eq. NaCl). These data may respond to a mixing between a low salinity fluid (fluid A, less than 5 wt.% eq. NaCl) and a more saline brine (fluid B, more than 25 wt.% eq. NaCl) at different fluid proportions

Sulfur and lead isotope systematics: Implications for the genesis of the Riópar Zn-(Fe-Pb) carbonate-hosted deposit (Prebetic Zone, SE Spain)

The Zn-(Fe-Pb) deposits of the Riópar area (Prebetic Zone, SE Spain) are hosted by dolostones that replace Berriasian to Valanginian (Upper Jurassic-Lower Cretaceous) limestones. Mineralization consists of hypogene sphalerite, marcasite and galena, and supergene calamine zones. The hypogene ores are associated with a saddle dolomite gangue. The ore bodies occur as discordant and stratiform lenses, ore-cemented breccias, cm- to mm-wide veins and veinlets, disseminations and stylolite porosity filling within the host dolomites. The main ore controls include stratigraphy and/or lithology, tectonics (faults, fractures and breccias) and availability of metals and sulfur. The morphologies and epigenetic character of the hypogene ore bodies are consistent with the classification of this mineralization as a Mississippi Valley-type (MVT) deposit. The Ga/Ge geothermometer in sphalerite yielded a temperature range of 194-252ºC, which represents the temperature of the source region of the ore solution. This value is comparable to the temperature obtained in the ore deposition site, 159±15ºC from the Δ34S geothermometer in sphalerite galena pairs. This similitude points to a hydrothermal fluid that did not cool down significantly during flow from the fluid reservoir area to the precipitation site. δ34S values of base-metal sulfides (-7.5 to +3.5 ¿) are consistent with thermochemical reduction of Triassic sulfate (seawater and/or derived from dissolution of evaporites) by interaction with organic compounds (e.g., hydrocarbons, methane), which reduced sulfate to sulfide in the deposition site. The lead isotope ratios (206Pb/204Pb = 18.736-18.762; 207Pb/204Pb = 15.629-15.660; 208Pb/204Pb = 38.496-38.595) of galena suggest that Pb, and probably other metals as Zn, is derived from continental crustal rocks. On the other hand, these relations points to an unique metal source probably derived from the Paleozoic basement rocks. The relationship between bedding-parallel stylolites, dolomitization, sulfide precipitation and Alpine tectonic affecting the MVT ore, suggests a relative timing range for the mineralization in the Riópar area of 95 to 20 Ma (Upper Cretaceous-Tertiary). The sulfide mineralization and the associated dolomitization are thus explained by the contribution of two fluids that mixed in different proportions during dolomitization and mineralization: i) a fluid probably derived from Cretaceous seawater saturating Mesozoic sediments (Fluid A), characterized by being dilute and initially low temperature, which should have contained organic rich compounds in the ore deposition site (e.g., hydrocarbons and CH4 dissolved gas); and ii) a high salinity hydrothermal brine (Fluid B) rich in both metals and sulfate, circulated through the Paleozoic basement. During the pre-ore dolomitizing stage the fluid phase was dominated by the diluted fluid (Fluid A > Fluid B), whereas in a later fluid pulse, the proportion of the high salinity fluid increased (Fluid A < Fluid B) which allowed sulfide precipitation. MVT exploration in the Prebetic Zone should focus towards the SW of the Riópar mines, in the vicinity of the Alto Guadalquivir-San Jorge fault

Dolomitization Related to Zn-(Pb) Deposits in the Río Mundo Area (Riópar, Albacete)

España. Ministerio de Economía y CompetitividadDepto. de Mineralogía y PetrologíaFac. de Ciencias GeológicasTRUEpu