Cytokines in clinical cancer immunotherapy Berraondo, Pedro; Sanmamed, Miguel F; Ochoa, María C ...
British journal of cancer,
01/2019, Letnik:
120, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical ...research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
Aims and objectives
To evaluate compassion fatigue (CF), burnout (BO), compassion satisfaction (CS) and perceived stress in healthcare professionals during the coronavirus disease 2019 (COVID‐19) ...health crisis in Spain.
Background
Spain has been one of the countries hardest hit by the health crisis caused by the COVID‐19 pandemic. Healthcare professionals have had to deal with traumatic and complex situations in the work context. In these particularly stressful situations, many professionals may develop CF or BO, which puts them at risk for mental health problems.
Design
Cross‐sectional online survey.
Methods
A total of 506 healthcare professionals (physicians and nurses) who were working in healthcare centres during the COVID‐19 pandemic participated. CF, CS and BO were assessed with the Professional Quality of Life Questionnaire, and perceived stress was measured with the Perceived Stress Scale‐14. Socio‐demographic and occupational variables were also analysed. Data were collected during the period of the highest incidence of cases and highest mortality rates due to COVID‐19 in Spain. This article adheres to the STROBE guidelines for the reporting of observational studies.
Results
Physicians had higher CF and BO scores, while nurses had higher CS scores. Perceived stress scores were similar in both occupations. Professionals working in specific COVID‐19 units and in emergency departments had higher CF and BO scores, while levels of CS and perceived stress were similar regardless of the workplace.
Relevance to clinical practice
Despite the health crisis situation and its implications for healthcare professionals, the levels of CF and BO have remained moderate/high. However, CS seems to be increasing, especially among nurses, possibly due to their motivation to relieve suffering and due to their perceived social recognition. It is necessary to implement interventions that help improve CS and prevent BO and CF among professionals in the long term.
Ionic liquids (ILs) are being widely used in many diverse areas of social interest, including catalysis, electrochemistry, etc. However, issues related to hygroscopicity of many ILs and the toxic ...and/or nonbiodegradable features of some of them limit their practical use. Developing materials capable of IL recovery from aqueous media and dehydration, thus allowing their recycling and subsequent reutilization, in a single and efficient process still poses a major challenge. Herein, electrically conductive aerogels composed of carbon nanofibers (CNFs) with remarkable superhydrophobic features are prepared. CNF‐based 3D aerogels are prepared through a cryogenic process, so called ice‐segregation‐induced self‐assembly (ISISA) consisting of the unidirectional immersion of an aqueous chitosan (CHI) solution also containing CNFs in suspension into a liquid nitrogen bath, and subsequent freeze‐drying. The CNF‐based 3D aerogels prove effective for absorption of ILs from aqueous biphasic systems and recovery with quite low water contents just through a single process of filtration. Moreover, the electrical conductivity of CNF‐based 3D aerogels is particularly interesting to treat highly viscous ILs because the Joule effect allows not only shortening of the absorption process but also enhancement of the flux rate when operating in flow‐through conditions.
Minimizing the environmental impact coming from the spread use of ionic liquids (ILs) requires their recovery from aqueous media. Reutilization of ILs also requires dehydration given their hygroscopic nature. Thus, filtration through a monolithic column offers an interesting alternative, mainly if the column is electrically conductive so the Joule effect allows high flux rates to be obtained even for highly viscous ILs.
Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and ...granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
Display omitted
•Tumor-secreted CXCR1 and CXCR2 ligands induce extrusion of NETs•NETs protect tumor cells from CTL and NK cytotoxicity in 3D cultures•Inhibition of NETosis sensitizes tumors to PD-1+CTLA-4 dual checkpoint blockade•NETs impair contact of immune cytotoxic cells with tumor cells in living mice
Extrusion of neutrophil extracellular traps (NETs) constitutes an adhesive mechanism employed by polymorphonuclear leukocytes in microbial defense and plays a role in cancer metastasis. Teijeira et al. show that intratumoral NETs protect malignant cells against cytotoxic attacks of the immune system, such as those elicited by checkpoint-based immunotherapy.
Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into ...tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes.
Abstract
The coronavirus pandemic has exposed healthcare professionals to suffering and stressful working conditions. The aim of this study was to analyze professional quality of life among ...healthcare professionals and its relationship with empathy, resilience, and self‐compassion during the COVID‐19 crisis in Spain. A cross‐sectional study was conducted with 506 healthcare professionals, who participated by completing an online questionnaire. A descriptive correlational analysis was performed. A multivariate regression analysis and a decision tree were used to identify the variables associated with professional quality of life. Empathy, resilience, and mindfulness were the main predictors of compassion fatigue, compassion satisfaction, and burnout, respectively.
To gain mechanistic insights into the acetate-assisted cyclometallations of arylimines promoted by RuCl
(
-cymene)
in polar protic media, DFT geometry optimizations (with M06 and
B97X-D3 functionals ...and the cc-pVDZ-PPRu basis set) followed by DLPNO-CCSD(T)/CBS energy evaluations were performed using benzaldimine as a model substrate and methanol as the solvent (with CPCM or SMD models). The calculation results show that coordination of the imine to an acetate ruthenium precursor is followed by anion (chloride or acetate) dissociation as the rate-determining step of the process. H-Bonding of two explicit MeOH to the anion reduces the calculated activation energy to
23 kcal mol
, in good agreement with the experimental half-life at room temperature. Subsequent AMLA/CMD C-H activation of the intermediate cationic complexes is a faster, reversible process. Alternative reaction pathways involving neutral diacetate ruthenium complexes offer AMLA/CMD transition state structures of lower energy but are precluded due to higher energy barriers for the initial ligand exchange processes at ruthenium. Solvent assistance accelerates the final chloride/acetate exchange processes on the cycloruthenate intermediates, particularly when compression in the condensed phase is taken into consideration. The performance of six DFT functionals (with the aug-pVTZ-PPRu basis set) was assessed using the DLPNO-CCSD(T)/CBS reference energies. Neutral diacetate ruthenium complexes were incorrectly predicted as being kinetically relevant when using hybrid DFT methods (PBE0-D3(BJ), M06-2X or
B97M-V). Good agreement between the calculated barrier heights and our benchmark energy results was obtained by using double-hybrid DFT methods. PWPB95 with D3(BJ) or D4 dispersion energy corrections was found to be the most accurate (Δ
MUE of
. 1 kcal mol
). This study may aid our understanding of and help with further experimental investigations of synthetically useful carboxylate-assisted C-H bond functionalizations involving (
,
)-cyclometallated (
-cymene)Ru(II) intermediate complexes in sustainable polar protic solvents.
The common use of Li-ion batteries (LIBs) in portable devices and electric vehicles is promoting an exponential growth of the rechargeable batteries market. Their use in electric vehicles while not ...yet so common will be favored in the near future by government incentives aiming to mitigate global warming effects coming from combustion engines. Despite the remote risk of cobalt (Co) and lithium (Li) supplies running low, metals recovery from “postconsumer” scrap is a rapidly expanding topic in the political agenda within the context of the circular economy. Among other recycling technologies, processes using mild conditions and providing high recycling efficiencies are gaining increased interest. For instance, organic acids are particularly interesting for LiCoO2 dissolution even though they typically need the additional use of reducing agents. Herein, we explore the Co (and Li) recovery from spent LIBs using deep eutectic solvents (DESs) at temperatures as low as 90 °C, at times of dissolution as short as 15 min and without the use of any additional reducing agent. In particular, we used the eutectic mixture composed of p-toluenesulfonic acid (PTSA) monohydrate and choline chloride (ChCl) (e.g., PTSA·H2O·ChClDES with a 1:1:1 molar ratio) and aqueous dilutions thereof (e.g., PTSA·2H2O·ChClDES and PTSA·3H2O·ChClDES with 1:2:1 and 1:3:1 molar ratios, respectively). Compared to organic acids, PTSAChCl-based DESs offered a significant reduction of the solute to solvent ratio (in g/L) needed for full Co dissolution. This brings benefits both in economic and sustainable terms that handling low solvent volumes has in industrial processes. Interestingly, Co recovery efficiencies from spent LIBs reached figures of up to 94% over the whole process relating to the extraction from spent LIBs using PTSAChCl-based DESs, the precipitation with either Na2CO3 or (NH4)2CO3, and the final calcination to obtain Co3O4.
•IL-8 is a chemokine frequently produced in the tumor microenvironment by human malignant cells.•IL-8 plays key roles in the immunobiology of human malignancies and resistance to ...treatments.•Circulating IL-8 concentration reflects tumor burden.•Change in serum IL-8 is a biomarker to follow immunotherapy with checkpoint inhibitors.
Interleukin-8 (CXCL8) was originally described asa chemokine whose main function is the attraction of a polymorphonuclear inflammatory leukocyte infiltrate acting on CXCR1/2. Recently, it has been found that tumors very frequently coopt the production of this chemokine, which in this malignant context exerts different pro-tumoral functions. Reportedly, these include angiogenesis, survival signaling for cancer stem cells and attraction of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. Given the fact that in cancer patients IL-8 is mainly produced by tumor cells themselves, its serum concentration has been shown to correlate with tumor burden. Thus, IL-8 serum concentrations have been shown to be useful asa pharmacodynamic biomarker to early detect response to immunotherapy. Finally, because of the roles that IL-8 plays in favoring tumor progression, several therapeutic strategies are being developed to interfere with its functions. Such interventions hold promise, especially for therapeutic combinations in the field of cancer immunotherapy.
PDF
