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Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of [CD4.sup.+] T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified [EBNA1.sub.567-581], a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both [CD4.sup.+] and [CD8.sup.+] T cells and recognizes HLA-DP5-restricted [EBNA1.sub.567-581]. TCR135-transduced T cells functioned in two ways: directly killing [HLA-DP5.sup.+][EBNA1.sup.+] tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen- presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in [HLA-DP5.sup.+] patients., Introduction Recent advances in immunotherapy have shown promising results in the treatment of solid tumors. Adoptive transfer of T cell receptor- engineered (TCR-engineered) T cells (TCR-T) is a promising approach [...]

Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression., Introduction Immunosuppression is crucial in solid organ transplantation to prevent allograft rejection. Current approaches involve combinations of drugs targeting different immune components. These include calcineurin inhibitors (e.g., tacrolimus), antiproliferative agents [...]

Introduction Recent studies have reported that ferroptosis is an iron-dependent cell death process and is a potential therapeutic target in various tumours. The purpose of this study was to establish a new algorithm based on the ferroptosis score to ascertain the prognosis and response to immunotherapy of patients with lung squamous cell carcinoma (LUSC). Methods The RNA-seq data of patients with LUSC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases and merged after removing the inter batch differences. Based on the expression of the ferroptosis-related genes, unsupervised consistent cluster analysis was performed to obtain various ferroptosis-related subgroups. These subgroups were analysed to obtain differentially expressed genes (DEGs). Subsequently, multiple gene clusters were obtained by unsupervised consistent cluster analysis based on the expression of the DEGs. The Boruta algorithm was used to calculate the ferroptosis score. Results There were significant differences in prognosis amongst the various ferroptosis-related and gene clusters. In addition, the gene set variation analysis revealed that the different ferroptosis-related clusters and gene clusters demonstrated differences in biological pathways. The ferroptosis scores positively correlated with the tumour mutation burden, and patients with lower scores had a better prognosis. In addition, the ferroptosis score was accurate in predicting the effectiveness of immunotherapy. Conclusion There were significant differences in the prognosis and immunotherapy response of patients with LUSC with different ferroptosis scores. Therefore, a comprehensive clinical evaluation of the ferroptosis score of each patient with LUSC is clinically significant., Author(s): Yinhe Feng [sup.1], Xingyu Xiong [sup.2], Yubin Wang [sup.3], Ding Han [sup.1], Chunfang Zeng [sup.1], Hui Mao [sup.3] Author Affiliations: (1) Department of Respiratory and Critical Care Medicine, People's [...]

Purpose Transport of secretory immunoglobulin A (SIgA) through the airway epithelial cell barrier into the mucosal lumen by the polymeric immunoglobulin receptor (pIgR) is an important mechanism of respiratory mucosal host defense. Identification of immunomodulating substances that regulate secretory immunity might have therapeutic implications with regard to an improved immune exclusion. Thus, we sought to analyze secretory immunity under homeostatic and immunomodulating conditions in different compartments of the murine upper and lower respiratory tract (URT&LRT). Methods Pigr gene expression in lung, trachea, and nasal-associated lymphoid tissue (NALT) of germ-free mice, specific pathogen-free mice, mice with an undefined microbiome, as well as LPS- and IFN-[gamma]-treated mice was determined by quantitative real-time PCR. IgA levels in bronchoalveolar lavage (BAL), nasal lavage (NAL), and serum were determined by ELISA. LPS- and IFN-[gamma]-treated mice were colonized with Streptococcus pneumoniae and bacterial CFUs were determined in URT and LRT. Results Respiratory Pigr expression and IgA levels were dependent on the degree of exposure to environmental microbial stimuli. While immunostimulation with LPS and IFN-[gamma] differentially impacts respiratory Pigr expression and IgA in URT vs. LRT, only prophylactic IFN-[gamma] treatment reduces nasal colonization with S. pneumoniae. Conclusion Airway-associated secretory immunity can be partly modulated by exposure to microbial ligands and proinflammatory stimuli. Prophylactic IFN-[gamma]-treatment modestly improves antibacterial immunity in the URT, but this does not appear to be mediated by SIgA or pIgR., Author(s): Alexander Pausder [sup.1] [sup.2] [sup.3], Jennifer Fricke [sup.4] [sup.9], Klaus Schughart [sup.4] [sup.5] [sup.6], Jens Schreiber [sup.7], Till Strowig [sup.8], Dunja Bruder [sup.1] [sup.2], Julia D. Boehme [sup.1] [sup.2] [...]

Background Accounting for 14% of lung cancer, small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid proliferation, early spread, and poor survival. Aim and Methods We provide an overview of recent advances regarding SCLC pathogenesis, subtypes, and treatment development through literature review of key trials. Results There are no validated biomarkers or approved targeted treatments for this overly heterogeneous disease, but recent analyses have identified some promising targets and four major subtypes which may carry unique therapeutic vulnerabilities in SCLC. Treatment wise, only a third of patients present with limited stage SCLC, which can be managed with a combined modality approach with curative intent (usually chemo-radiotherapy, but in some eligible patients, surgery followed by systemic treatment). For advanced or extensive stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard front-line treatment, with modest improvement in overall survival. In the second-line setting, for disease relapse [less than or equal to] 6 months, topotecan, lurbinectedin, and clinical trials are reasonable treatment options; for disease relapse > 6 months, original regimen, topotecan or lurbinectedin can be considered. Moreover, Trilaciclib, a CD4/CD6 inhibitor, was recently FDA-approved to decrease the incidence of chemotherapy-related myelosuppression in SCLC patients. Conclusions While modest improvements in survival have been made especially in the metastatic setting with chemo-immunotherapy, further research in understanding the biology of SCLC is warranted to develop biomarker-driven therapeutic strategies and combinational approaches for this aggressive disease., Author(s): Sara Tariq [sup.1], So Yeon Kim [sup.1], Jose Monteiro de Oliveira Novaes [sup.2], Haiying Cheng [sup.1] Author Affiliations: (1) grid.240283.f, 0000 0001 2152 0791, Department of Medical Oncology, Montefiore [...]

Tumor immunosuppression is a limiting factor for successful cancer therapy. The lipid sphingosine-1-phosphate (S1P), which signals through 5 distinct G protein-coupled receptors (S1PR1-5), has emerged as an important regulator of carcinogenesis. However, the utility of targeting S1P in tumors is hindered by S1P's impact on immune cell trafficking. Here, we report that ablation of the immune cell-specific receptor S1PR4, which plays a minor role in immune cell trafficking, delayed tumor development and improved therapy success in murine models of mammary and colitis-associated colorectal cancer through increased [CD8.sup.+] T cell abundance. Transcriptome analysis revealed that S1PR4 affected proliferation and survival of [CD8.sup.+] T cells in a cell-intrinsic manner via the expression of Pik3ap1 and Lta4h. Accordingly, PIK3AP1 expression was connected to increased [CD8.sup.+] T cell proliferation and clinical parameters in human breast and colon cancer. Our data indicate a so-far-unappreciated tumor-promoting role of S1P by restricting [CD8.sup.+] T cell expansion via S1PR4., Introduction The impact of the immune system on tumor progression is multifaceted. Although inflammation may promote cancer progression, data obtained from animal models and clinical studies demonstrate that the immune [...]

As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFN-[gamma] typically helps microbial clearance, we found that increased plasma IFN-[gamma] in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-[gamma] suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-[gamma] after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-[gamma] production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in [Cd1d.sup.-/-] mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-[gamma] axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-[gamma], which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality., Introduction In sepsis, an excessive inflammatory response to infection leads to end organ damage (1). After surviving the early, inflammatory phase of sepsis, previously healthy patients can develop post-sepsis immunosuppression [...]

Scorpion envenomation is common in the tropical and subtropical regions. It poses a major public health problem with some patients having serious clinical manifestations and severe complications including death. Old World and New World scorpions are usually contrasted because of differences in venom composition, clinical presentation and severity, and, accordingly, different therapeutic approaches. The majority of scorpion stings are either dry or result in low amounts of injected venom, thus explaining why up to 95% of scorpion stings ensue only in local signs. For a clinical envenomation to occur, it has been suggested that the interaction between the quantity of venom introduced in the body of the prey and the distribution volume should ensue in a critical threshold of scorpion toxin plasma concentration. In this case, there is a massive release of neurohormonal mediators (mainly catecholamine), with systemic vasoconstrictor effects eliciting a sharp increase in systemic arterial pressure and LV-filling pressure and decreased cardiac output. This early phase of cardiac dysfunction, also called 'vascular phase', is followed by a severe cardiomyopathy, a form of Takotsubo cardiomyopathy, involving both ventricles and reversible in days to weeks. The more comprehensive understanding of the disease pathophysiology has allowed for a well-codified symptomatic treatment, thus contributing to a substantial reduction in the death toll of scorpion envenomation over the past few decades. The standard intensive-care treatment (when available) overcomes envenomation's consequences such as acute pulmonary edema and cardiogenic shock. Even though it continues to inspire many evaluative studies, immunotherapy seems less attractive because of the major role held by mediators in the pathogenesis of envenomation, and unfavorable pharmacokinetic properties to existing sera compared to venom. Meta-analyses of controlled trials of immunotherapy in severe scorpion envenomation reached similar conclusions: there is an acceptable level of evidence in favor of the use of scorpion antivenom (Fab'.sub.2) against Centruroides sp. in USA/Mexico, while there is still a need for a higher level of evidence for immunotherapy in the Old World envenomation., Author(s): Fekri Abroug [sup.1] [sup.2], Lamia Ouanes-Besbes [sup.1] [sup.2], Nejla Tilouche [sup.2] [sup.3], Souheil Elatrous [sup.2] [sup.3] Author Affiliations: (1) grid.411838.7, 0000 0004 0593 5040, Intensive Care Unit, CHU F. [...]

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Ape-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs., Introduction Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide (1). Patients with stage III or IV CRC have a high risk of recurrence and are [...]

BACKGROUND. Chronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific [CD4.sup.+] T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific [CD4.sup.+] T cells after virus elimination. METHODS. HCV-specific [CD4.sup.+] T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with directacting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed. RESULTS. We observed that the frequency of HCV-specific [CD4.sup.+] T cells increased within 2 weeks after initiating directacting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific [CD4.sup.+] T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity. CONCLUSION. We identified a population of HCV-specific [CD4.sup.+] T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections. FUNDING. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS., Introduction The development and approval of direct-acting antivirals (DAAs) targeting different viral proteins of the hepatitis C virus (HCV) has revolutionized the treatment of millions of chronically infected individuals worldwide [...]

Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic [CD8.sup.+] DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43- containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction-mediated Ag transfer pathway between monocytes and [CD8.sup.+] DCs and suggest that administration of tumor Ag-loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers., Introduction A major approach to cancer immunotherapy is the use of cellular vaccines to induce cytotoxic T lymphocyte (CTL) responses against specific tumor antigens (Ags) (1, 2). Among tumor vaccine [...]

Purpose Severe immune dysregulation is common in patients admitted to the intensive care unit (ICU) and is associated with adverse outcomes. Erythropoietin-stimulating agents (ESAs) have immune-modulating and anti-apoptotic effects. However, their safety and efficacy in critically ill patients remain uncertain. We evaluated whether ESAs, administered to critically unwell adult patients admitted to the ICU, reduced mortality at hospital discharge. Methods The search strategy was conducted according to a predetermined protocol and included OVID MEDLINE, OVID EMBASE and The Cochrane Central Register of Controlled Trials from inception until 20 May 2019. Publications were eligible for inclusion if they were randomized controlled trials (RCTs) including adult patients admitted to an ICU, that identified and reported a group receiving ESA therapy compared to a group not receiving ESA therapy and reported mortality. There were no language restrictions. Results The systematic review included 21 studies with 5452 participants. In-hospital mortality, reported in 16 studies of which only one was at low risk of bias, was lower in the ESA group (276 of 2187 patients, 12.6%) than the comparator group (339 out of 2204 patients, 15.4%), [relative risk (RR) 0.82, 95% CI 0.71-0.94, P = 0.006, I.sup.2 = 0.0%]. The RR of SAEs and thromboembolic events for the ESA and comparator groups were similar, RR 1.11 (95% CI 0.94-1.31, P = 0.228, I.sup.2 66%) and 1.22 (95% CI 0.95-1.58, P = 0.086, I.sup.2 47%), respectively. Conclusions In heterogenous populations of critically ill adults, evidence from RCTs of mainly low or unclear quality, suggests that ESA therapy may decrease mortality., Author(s): Edward Litton [sup.1] [sup.2], Peter Latham [sup.3], Julia Inman [sup.4], Jingjing Luo [sup.5], Peter Allan [sup.6] Author Affiliations: (1) Intensive Care Unit, St John of God Hospital Subiaco, , [...]

Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration. We observed increased SCLC survival following intrapulmonary MYXV that was enhanced by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and observed immune cell infiltration associated with tumor necrosis and growth inhibition in syngeneic murine allograft tumors. Freshly collected primary human SCLC tumor cells were permissive to MYXV and intratumoral delivery into patient-derived xenografts resulted in extensive tumor necrosis. We confirmed MYXV cytotoxicity in classic and variant SCLC subtypes as well as cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible immune cell infiltration, supporting testing MYXV as an ablative and immune-enhancing therapy., Introduction Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype that was recently selected by the National Cancer Institute, NIH, for a focused strategic plan due to its high incidence [...]

Purpose The definitions of sepsis and septic shock have recently been revised in adults, but contemporary data are needed to inform similar approaches in children. Methods Multicenter cohort study including children 2 mmol/l discriminated poorly (AUC Conclusions We observed mortality patterns specific to pediatric sepsis that support the need for specialized definitions of sepsis severity in children. We demonstrated the importance of lactate, cardiovascular, and respiratory derangements at ICU admission for the identification of children with substantially higher risk of sepsis mortality., Author(s): Luregn J. Schlapbach [sup.1] [sup.2] [sup.3], Graeme MacLaren [sup.4] [sup.5], Marino Festa [sup.6], Janet Alexander [sup.7] [sup.8], Simon Erickson [sup.9], John Beca [sup.10], Anthony Slater [sup.2], Andreas Schibler [sup.1] [...]

Purpose This prospective observational study aimed at describing prescription patterns of tigecycline and patient outcomes in 26 French intensive care units (ICU). Methods Data of consecutive cases of adult patients treated with tigecycline were collected from the initiation until 7 days after the end of treatment. Response to treatment was classified as success, failure or undetermined and analyses were presented according to severity (SOFA score Results A total of 156 patients were included (64 % male, age 60 ± 15 years). At inclusion, 53 % had a SOFA score [greater than or equal to]7; 93 % had received prior anti-infective agents. Tigecycline was given as first-line treatment in 47 % of patients, mostly in combination (67 %), for intra-abdominal (IAI 56 %), skin and soft tissue (SSTI 19 %) or other infections. A total of 76 % of the treated infections were hospital-acquired. Bacteraemia was reported in 12 % of patients. Median treatment duration was 9 days. Tigecycline was prematurely stopped in 42 % patients. The global success rate was 60 % at the end of treatment, and significantly higher with treatment duration more than 9 days (76 vs. 47 %, P < 0.001). Success rate was 65 % for patients alive at the end of treatment. Success rates tended to decrease with illness severity, immunosuppression, bacteraemia and obesity. Survival rate at day 28 was 85 % in the whole cohort and significantly higher in the less severely ill patients (P < 0.001). Conclusions Tigecycline success rates appear comparable to those reported in clinical studies in ICU with severe infections. Tigecycline could be an alternative in ICU patients., Author(s): Philippe Montravers [sup.1], Hervé Dupont [sup.2], Jean-Pierre Bedos [sup.3], Philippe Bret [sup.4] Author Affiliations: (1) grid.7452.4, 0000000122170017, Department of Anesthesiology and Surgical Intensive Care, Bichat-Claude Bernard University Hospital Center, [...]