New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis

CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.I.M. has been granted with PID2020-112892RB funded by MICIN/AEI/10.13039/501100011033 and SAF2017-83267-C2-1-R funded by MICIN/AEI/10.13039/501100011033/ and by FEDER “Una manera de hacer Europa,” (HR21-00083) the Fundación La Caixa, “MINCITH. Metabolic requirements for immune INfiltration in effective Cancer ImmunoTHerapy” “AYUDAS FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACIÓN CIENTÍFICA 2019” Fundación BBVA, the Instituto de Salud Carlos III (PI20/00002 and PI19/01128), cofinanced by the Fondos FEDER “A way to make Europe” and Joint Translational Call for Proposals 2015 (JTC 2015), TRANSCAN456 2 (code TRS-2016-00000371), and the Gobierno de Navarra Proyecto LINTERNA (reference 0011-1411-2020-000075). Funding was also received from B. J. Baselga (Fundación FERO) and the T2-EVOLVE project from the EU. I.M. and M.A. receive grant funding from Pharmamar and Highlight Therapeutics. M.A. is supported by AECC (INVES1904ALVA). J.M.Z. has been granted with PID2019-110405RB-I00 funded by MICIN/AEI/10.13039/501100011033 and with P2022/BMD-7225 funded by Consortium in Biomedicine of Comunidad de Madrid.Peer reviewe

Reduction of the frequency of herbaceous roots as an effect of soil compaction induced by heavy grazing in rangelands of SW Spain

Rangelands in SW Spain constitute the most extensive ranching system on the Iberian Peninsula. During the last few decades, a significant increase in livestock numbers, along with a progressive substitution of cattle for sheep, have led to land degradation processes such as the reduction of grass cover and increased soil compaction in heavily grazed areas. Nevertheless, a better understanding of how soil compaction affects grass production is still needed. In this study, some of the effects of soil compaction due to heavy grazing are analysed, mainly the reduction of the frequency of herbaceous roots and its relationships with bulk density and soil penetration resistance. The study was carried out in 22 fenced areas grazed under different intensities (animal stocking rates: 0.19-15.76 AU ha−1). Undisturbed soil core and bulk samples were collected at 3 depth intervals in order to determine select soil properties (texture, organic matter content, and bulk density). Additionally, soil penetration resistance was quantified at 890 random points at different depths and soil moisture contents. Frequency of herbaceous roots was estimated for each soil horizon in 47 soil profiles and categorized into 4 classes: none, few, common and many. Results showed negative relationships between bulk density (> 10 cm depth) and the content of soil organic matter from 0 to 5 cm (r =−0.061, p < 0.05) and 5-10 m depth (r = −0.824, p < 0.005). Furthermore, a tendency for decreasing mean values of soil penetration resistance as the frequency of herbaceous roots increased was also observed. The values observed confirm that soil compaction provoked by an excessive number of animals reduced the quantity of herbaceous roots. The value of 2 MPa traditionally accepted as restrictive for root growth is discussed. Findings presented here could be of interest for policy makers and farm owners to guide decisions about optimum animal stocking rates

Measurement of the 244^{244}Cm and 246^{246}Cm Neutron-Induced Cross Sections at the n_TOF Facility

The neutron capture reactions of the $^{244}$Cm and $^{246}$Cm isotopes open the path for the formation of heavier Cm isotopes and of heavier elements such as Bk and Cf in a nuclear reactor. In addition, both isotopes belong to the minor actinides with a large contribution to the decay heat and to the neutron emission in irradiated fuels proposed for the transmutation of nuclear waste and fast critical reactors. The available experimental data for both isotopes are very scarce. We measured the neutron capture cross section with isotopically enriched samples of $^{244}$Cm and $^{246}$Cm provided by JAEA. The measurement covers the range from 1 eV to 250 eV in the n_TOF Experimental Area 2 (EAR-2). In addition, a normalization measurement with the $^{244}$Cm sample was performed at Experimental Area 1 (EAR-1) with the Total Absorption Calorimeter (TAC)

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis

CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development

mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy

Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previ-ously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their sys-temic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to ex-press either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly in-jected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitu-lated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL -12 and DRIL18 mRNA electroporation

Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants

Background Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2 ' 3 '-cyclic GMP-AMP (2 ' 3 '-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism. Methods Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2 ' 3 '-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed. Results Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy