Immunological Intervention Research Articles

Sex Differences in the Systemic and Local Immune Response of Pancreatic Cancer Patients

Mounting evidence suggests that sex plays a critical role in various aspects of cancer such as immune responses. However, a male bias exists in human and non-human studies including immunotherapy trials. The role of sex on immune responses in pancreatic ductal adenocarcinoma (PDA) is unclear. Here, tumor tissues (tumor and stroma separately) and corresponding blood samples from patients with PDA (n = 52) were systematically analyzed by immunohistochemistry and multiplex cytokine measurements and compared by sex. Females showed a stronger systemic immune response with higher levels of CXCL9, IL1B, IL6, IL10 and IL13. Additionally, more peripheral white blood cells were detected in females. In the microenvironment, males showed higher tumoral levels of CXCL12. No differences were detected in the stroma. Females showed a tendency towards an anti-tumoral immune cell profile. CXCL12 blockade indicated a differential microenvironmental effect by sex in an independent immunotherapy trial cohort of patients with PDA (one female, five males). The overall survival did not differ by sex in our cohort. Systemic and local immune responses differ between sexes in PDA. Accordingly, sex-dependent differences need to be considered in human studies and for specific immunological interventions before clinical translation.

Mining chicken ileal microbiota for immunomodulatory microorganisms.

The gut microbiota makes important contributions to host immune system development and resistance to pathogen infections, especially during early life. However, studies addressing the immunomodulatory functions of gut microbial individuals or populations are limited. In this study, we explore the systemic impact of the ileal microbiota on immune cell development and function of chickens and identify the members of the microbiota involved in immune system modulation. We initially used a time-series design with six time points to prove that ileal microbiota at different succession stages is intimately connected to immune cell maturation. Antibiotics perturbed the microbiota succession and negatively affected immune development, whereas early exposure to the ileal commensal microbiota from more mature birds promoted immune cell development and facilitated pathogen elimination after Salmonella Typhimurium infection, illustrating that early colonization of gut microbiota is an important driver of immune development. Five bacterial strains, Blautia coccoides, Bacteroides xylanisolvens, Fournierella sp002159185, Romboutsia lituseburensis, and Megamonas funiformis, which are closely related to the immune system development of broiler chickens, were then screened out and validated for their immunomodulatory properties. Our results provide insight into poultry immune system-microbiota interactions and also establish a foundation for targeted immunological interventions aiming to combat infectious diseases and promote poultry health and production.

Comprehensive analysis of BUBs gene family in lung adenocarcinoma with immunological analysis.

Lung adenocarcinoma (LUAD) is one of the most commonly malignant tumors, and major challenges remain in the treatment of LUAD. Budding uninhibited by benzimidazole 1/3 (BUB1/3) play significant roles in the process of spindle-assembly checkpoint (SAC) during mitosis. However, their roles in LUAD have not been established. Here, we performed an immunological analysis of BUB1/3 in LUAD using a comprehensive bioinformatics approach, quantitative real-time-PCR and Western blotting technique. Our results indicated that the expression levels of BUB1 and BUB3 in LUAD samples were higher than the expression levels in the control groups and were associated with some clinicopathologic parameters in patients with LUAD. BUB1/3 and their related genes were enriched in cell immune, and the immune infiltration analysis revealed that the BUB1/3 expression profile was significantly correlated with characteristics of immune cell infiltration. Survival analysis showed that the disease-free survival and overall survival of patients with LUAD decreased with an increase in the BUB1/3 expression levels. The mRNA and protein expression levels of BUB1 and BUB3 in each of the LUAD cell lines were upregulated to varying degrees. BUB1 and BUB3 are the potential immunological therapeutic intervention targets for patients with LUAD.

Dual inhibition of complement C5 and CD14 attenuates inflammation in a cord blood model.

Escherichia coli and Group B streptococci (GBS) are the main causes of neonatal early-onset sepsis (EOS). Despite antibiotic therapy, EOS is associated with high morbidity and mortality. Dual inhibition of complement C5 and the Toll-like receptor co-factor CD14 has in animal studies been a promising novel therapy for sepsis. Whole blood was collected from the umbilical cord after caesarean section (n = 30). Blood was anti-coagulated with lepirudin. C5 inhibitor (eculizumab) and anti-CD14 was added 8 min prior to, or 15 and 30 min after adding E. coli or GBS. Total bacterial incubation time was 120 min (n = 16) and 240 min (n = 14). Cytokines and the terminal complement complex (TCC) were measured using multiplex technology and ELISA. Dual inhibition significantly attenuated TCC formation by 25-79% when adding inhibitors with up to 30 min delay in both E. coli- and GBS-induced inflammation. TNF, IL-6 and IL-8 plasma concentration were significantly reduced by 28-87% in E. coli-induced inflammation when adding inhibitors with up to 30 min delay. The dual inhibition did not significantly reduce TNF, IL-6 and IL-8 plasma concentration in GBS-induced inflammation. Dual inhibition of C5 and CD14 holds promise as a potential future treatment for severe neonatal EOS. Neonatal sepsis can cause severe host inflammation with high morbidity and mortality, but there are still no effective adjunctive immunologic interventions available. Adding CD14 and complement C5 inhibitors up to 30 min after incubation of E. coli or Group B streptococci in a human umbilical cord blood model significantly reduced complement activation and cytokine release. Dual inhibition of C5 and CD14 is a potential future therapy to modulate systemic inflammation in severe cases of neonatal sepsis.

The role of immune cells and mediators in preeclampsia.

Preeclampsia is a hypertensive disorder of major concern in pregnancy than can lead to intrauterine growth restriction, placental abruption and stillbirth. The pathophysiology of preeclampsia is multifactorial, including not only kidney dysfunction but also endothelial dysfunction, as the maternal endothelium becomes exposed to placental factors that are released into the circulation and increase systemic levels of vasoconstrictors, oxidative stress, anti-angiogenic factors and inflammatory mediators. Importantly, inflammation can lead to insufficient placental perfusion and low birthweight in offspring. Various innate and adaptive immune cells and mediators have been implicated in the development of preeclampsia, in which oxidative stress is associated with activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils are known to have major causative roles in the pathology of preeclampsia, but the contributions of additional immune cells such as B cells, inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies are also now recognized. Immunological interventions, therefore, have therapeutic potential in this disease. Here, we provide an overview of the immune responses that are involved in the pathogenesis of preeclampsia, including the role of innate and adaptive immune cells and mediators.

Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis.

Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.

How can an immunologist influence the occurrence of secondary infections in breast cancer? Real‑life study.

Clinical manifestation of secondary immunodeficiency is responsible for the decrease in lfe quality in cancer‑treated patients, which may result in administration delays, dose reductions, even in discontinuation of treatment. The main aim of presented study was to stress the possibility of influencing secondary infections with adjunctive immuno-regulatory medicament (AIRT). The presented real-life retrospective study involved a cohort of 94 adult female patients aged from 30 to 87 years with mean age of 58.4 (SD = 11.37). The cohort was divided into two groups. One group (54 patients; 57.45 %) was treated by using the adjunctive immuno-regulatory medicaments and the other, control group (40 patients; 42.55 %), was without any immunological interventions in relation to secondary immunodeficiency. Patients in both groups were treated by standard oncotherapy. The results show that in patients who were sent for immunological consultation, double-digit values of mild secondary infection frequencies were revealed. When immunologists decided to add adjunctive immunomodulatory medicament, the occurrence of infection and consumption of antibiotics decreased. The decrease was significant in the second evaluated interval (6th - 12th month). Our results strongly advise regular or even preventive examination of cancer patients by immunologic specialist for the purpose of attenuating some negative consequences of applied anti-tumor therapy (Tab. 1, Fig. 4, Ref. 14). Text in PDF www.elis.sk Keywords: secondary infection, breast cancer, real‑life study, clinical immunology, treatment.

EVALUATION OF THE ANTIBODY LEVELS AGAINST BCG AND POLYSACCHARIDES MENINGOCOCCAL VACCINES WHEN COMBINED, CO-ADMINISTRATED OR ADMINISTRATED AT DIFFERENT INTERVALS IN MURINE MODEL

Bacillus Calmette-Guerin (BCG) and polysaccharide meningococcal (pMen) vaccines are required to travel to some countries, medical staff to deal with disease carriers, and for special cases as well. However, there were not enough studies on the immunogenic intervention between them when given together or in combination. Hence, we tried to assess the antibody-mediated immune response in groups of mice when different BCG vaccines and pMen were combined or given together, either concurrently or with a 14-day break between them. The antibody titer was measured in each group after 21 and 42 days from the first injection. Our results showed that it was safe and effective to give these two vaccines combined or simultaneously. Moreover, they exhibited a potent synergistic effect even if there was a 14 days gap between their administration. However, more research is needed to investigate the immunological intervention's cellular-mediated response.

Management and prognosis of pediatric status epilepticus

Abstract Background Pediatric status epilepticus is a neurological emergency with the potential for severe developmental and neurological consequences. Prompt diagnosis and management are necessary. Objectives To outline the existing best available evidence for managing pediatric and neonatal status epilepticus, in the light of emerging randomized controlled studies. We also focus on short and long-term prognoses. Materials and methods This is a systematic overview of the existing literature. Results Status epilepticus, its treatment, and prognosis are usually based on the continuation of seizure activity at 5 and 30 min. Refractory and super-refractory status epilepticus further complicates management and requires continuous EEG monitoring with regular reassessment and adjustment of therapy. Benzodiazepines have been accepted as the first line of treatment on the basis of reasonable evidence. Emerging randomized controlled trials demonstrate equal efficacy for parenterally administered phenytoin, levetiracetam, and valproic acid as second-line agents. Beyond this, the evidence for third-line options is sparse. However, encouraging evidence for midazolam and ketamine exists with further data required for immunological, dietary, and surgical interventions. Conclusion Our overview of the management of pediatric and neonatal status epilepticus based on available evidence emphasizes the need for evidence-based guidelines to manage status epilepticus that fails to respond to second-line treatment.

Peripheral blood marker of residual acute leukemia after hematopoietic cell transplantation using multi-plex digital droplet PCR.

BackgroundRelapse remains the primary cause of death after hematopoietic cell transplantation (HCT) for acute leukemia. The ability to identify minimal/measurable residual disease (MRD) via the blood could identify patients earlier when immunologic interventions may be more successful. We evaluated a new test that could quantify blood tumor mRNA as leukemia MRD surveillance using droplet digital PCR (ddPCR).MethodsThe multiplex ddPCR assay was developed using tumor cell lines positive for the tumor associated antigens (TAA: WT1, PRAME, BIRC5), with homeostatic ABL1. On IRB-approved protocols, RNA was isolated from mononuclear cells from acute leukemia patients after HCT (n = 31 subjects; n = 91 specimens) and healthy donors (n = 20). ddPCR simultaneously quantitated mRNA expression of WT1, PRAME, BIRC5, and ABL1 and the TAA/ABL1 blood ratio was measured in patients with and without active leukemia after HCT.ResultsTumor cell lines confirmed quantitation of TAAs. In patients with active acute leukemia after HCT (MRD+ or relapse; n=19), the blood levels of WT1/ABL1, PRAME/ABL1, and BIRC5/ABL1 exceeded healthy donors (p<0.0001, p=0.0286, and p=0.0064 respectively). Active disease status was associated with TAA positivity (1+ TAA vs 0 TAA) with an odds ratio=10.67, (p=0.0070, 95% confidence interval 1.91 – 59.62). The area under the curve is 0.7544. Changes in ddPCR correlated with disease response captured on standard of care tests, accurately denoting positive or negative disease burden in 15/16 (95%). Of patients with MRD+ or relapsed leukemia after HCT, 84% were positive for at least one TAA/ABL1 in the peripheral blood. In summary, we have developed a new method for blood MRD monitoring of leukemia after HCT and present preliminary data that the TAA/ABL1 ratio may may serve as a novel surrogate biomarker for relapse of acute leukemia after HCT.

Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis.

Background/PurposeIn rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA.Materials and MethodsWe evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR).ResultsTwenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences.ConclusionThese findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.

Abstract 4254: ADT-010, a novel immunomodulatory antibody that harnesses the anti-tumor properties of tissue-resident Vδ1 γδ T cells

Abstract Background: Recent studies have highlighted the contribution of gamma delta (γδ) T cells in the immune response to cancer, and their infiltration in tumors is a positive prognostic factor. Vδ1 T cells are the most abundant γδ T cells in epithelial tissues including the gut and skin and form a significant proportion of tumour infiltrating lymphocytes (TILs) in a number of solid tumour indications. Tissue-resident cytotoxic Vδ1 γδ T cells are of particular interest in immunotherapy approaches for their role in recognising and eradicating cancer cells, providing new avenues for antibody tissue-based immunological intervention. Vδ1 γδ T cells combine features of innate and adaptive immunity: in contrast to αβ T cells that rely on antigen-presentation via MHC, γδ T cells recognize and kill transformed cells by direct recognition of a pattern of stress associated ligands expressed on their surface, opening up a potential range of cold tumours with decreased or impaired tumour antigen presentation. Adaptate’s first-in-class approach is to harness the specific anti-tumour properties of Vδ1 T cells using activating immunomodulatory antibodies. Methods: Adaptate’s ADT-010 is a first-in-class, fully human, monoclonal antibody which selectively recognizes and binds to the Vδ1 TCR leading to Vδ1 T cell activation. ADT-010 was selected via high-stringency antigen binding using a human phage display library. To elucidate its mechanism of action, the binding and functional activity of ADT-010 was evaluated on expanded skin-derived Vδ1 T cells in vitro. Results: ADT-010 specifically enhanced the Vδ1 killing of cancer cells whilst sparing healthy non-diseased cells. The functional activity of ADT-010 on expanded skin-derived Vδ1 T cells was investigated in the presence or absence of tumour cells. ADT-010 mediated activation of Vδ1 T cells in the presence of target tumour cells was demonstrated through TCR downregulation, CD107a and CD25 upregulation, and enhanced anti-tumour cytotoxicity. Taken together the data indicates that Vδ1 TCR engagement on γδ T cells by ADT-010 results in their full activation and enhanced cytotoxicity only in the presence of target tumour cells. Conclusions: Despite recent advances in immune therapies in oncology, there currently remains a significant unmet need for effective and safe treatments for solid tumours. The challenges of treating such tumours which include infiltration into the tumour tissue and discrimination between healthy and tumour cells have the potential to be addressed by novel approaches such as Adaptate’s ADT-010 antibody. ADT-010 specifically activates a population of tumour-resident Vδ1 T cells that can then orchestrate a potent and highly selective anti-tumour response through direct killing.Adaptate’s first-in-class ADT-010 is being progressed to the clinic for the treatment of solid tumour indications. Citation Format: Jose Munoz-Olaya, Aoife McGinley, Daniel Foxler, Samuel Samuel, Tanguy Lechertier, Shefali Bhumbra, Robert Good, Luke Cave, Oxana Polyakova, Mark Uden, Mihriban Tuna, Natalie Mount. ADT-010, a novel immunomodulatory antibody that harnesses the anti-tumor properties of tissue-resident Vδ1 γδ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4254.

Antigen and Immunogen: An Investigation into the Heterogeneity of Immunology Terminology in Learning Resources.

The need to focus on immunology education has never been greater. The coronavirus disease 2019 pandemic has revealed that a significant proportion of our society is vaccine hesitant. Some of this hesitancy may stem from a general lack of understanding of how the immune system and immunological interventions work. In addition, social media platforms undercut public health efforts by quickly propagating a multitude of misconceptions and erroneous information surrounding the science behind these interventions. The responsibility to be advocates for science is well recognized by immunology researchers, educators, and public health professionals, as evidenced by the rich body of resources developed to communicate science to the lay audience. Scientific jargon, however, can be a barrier to effective communication and can negatively impact learning and comprehension. The field of immunology is especially laden with discipline-specific terminology, which can hamper educators' efforts to convey key concepts to learners. Furthermore, a lack of consistency in accepted definitions can complicate students' conceptual understanding. Learning resources, including textbooks, published in print or available online, and exclusively digital resources, continue to serve as the primary sources of information for both educators and students. In this article, we describe a vast heterogeneity in learning resource glossary descriptions of two key conceptual terms: antigen and immunogen We provide a perspective on pedagogical strategies to address these critical terms. Using current knowledge, we recommend an approach to standardize the definitions of the terms antigen and immunogen within the immunology educator community.

Reducing the Damage of Ox-LDL/LOX-1 Pathway to Vascular Endothelial Barrier Can Inhibit Atherosclerosis.

Aim The destruction of the vascular endothelial barrier mediated by Ox-LDL is the initial link to atherosclerosis. Here, we aimed to determine whether the immunological intervention with Ox-ApoB polypeptide fragment (Ox-ApoB-PF) can block the deposition of Ox-LDL in vascular endothelial cells through LOX-1 receptors, thereby protecting the barrier function and survival status of vascular endothelial cells and inhibiting the progression of atherosclerosis. Methods and Results In order to determine the harm of Ox-LDL to vascular endothelial cells and the protective effect of immune intervention with Ox-ApoB-PF, we conducted a series of corresponding experiments in vitro and in vivo. The in vitro results showed that Ox-LDL can activate endothelial cell apoptosis pathway; reduce the expression of endothelial junction proteins; affect the migration, deformation, and forming ability; and ultimately destroy the vascular endothelial barrier function. The increased permeability of endothelial cells led to a sharp increase in the phagocytosis of Ox-LDL by macrophages under the endothelial layer. Meanwhile, Ox-LDL stimulation induced a significant upregulation of LOX-1 in endothelial cells and increased the expression of endothelial cell chemokines and adhesion factors. Ox-ApoB-PF antibodies can significantly reduce the abovementioned harmful effects. The in vivo results showed that active immune intervention through Ox-ApoB-PF can protect the endothelial barrier function; reduce macrophage deposition and the inflammatory response in plaques; alleviate lipid deposition in the plaques, as well as apoptosis and necrosis; and increase the ability of liver macrophages to clear Ox-LDL. Eventually, the progression of plaque and the formation of necrotic cores in plaques can be inhibited. Conclusions An Ox-ApoB-PF antibody may protect the endothelial cell physiological function and survival status by blocking the combination of Ox-LDL/LOX-1 in vascular endothelial cells. Immune intervention with Ox-ApoB-PF inhibits the occurrence and development of atherosclerotic lesions by protecting the vascular endothelial barrier function.

A commentary of “‘Shock and Kill’ of Latent HIV” : 10 remarkable discoveries from 2020 in Nature

HIV, the virus that causes acquired immunodeficiency syndrome (AIDS), can integrate into the genome of host cells and form latent reservoirs, making it undetectable by the immune system. Two studies published in Nature in January 2020 reported a ‘shock and kill’ strategy that aimed to activate the transcription of the latent reservoirs and render infected cells vulnerable to elimination by the immune system. Both study groups described interventions that were the most effective activation to date and were also reproducible. Nixon et al. used a drug called AZD5582 to activate the transcription of nuclear factor kappa B (NF-κB), a major inducer of HIV-1 gene expression [1] McBrien et al. combined two immunological interventions by first depleting CD8 T cells (immune cells that reduce the level of viral transcription) followed by treatment with a drug called N-803, which activated HIV-1 transcription [2]. In addition to these advances, these two studies also demonstrated the conceptual and technical challenges of pharmacological latency reversal.①①Original source in Chinese: L. Zhang, Y. Li, “Shock and Kill” of Latent HIV, Bulletin of National Natural Science Foundation of China. 35 (2) (2021) 241-242

Immunological, Physical, and Psychological Interventions in Young-Onset Stiff-Person Syndrome.

Immunological, Physical, and Psychological Interventions in Young-Onset Stiff-Person Syndrome.

Geolocated Wireless Heart Rate Variability Sentinel Surveillance in Immunological Assessment, Intervention and Research Concerning COVID-19 and other Pandemic Threats

With the development of increasingly sophisticated biotechnology and conceptual/analytic approaches, a greater ability to understand, intervene and prevent disease and promote health is becoming more available. A synthetic integration of several such technologies and analytic strategies named the Canary System is described which can impact significant global health problems, including the COVID-19 pandemic with its continuously evolving variants. The system wirelessly acquires high fidelity heart rate variability and other data, geocodes the data and transfers It through personal device for high throughput algorithmic analysis, which has been shown to indicate likely COVID-19 status well before clinical symptoms emerge, if indeed the individual becomes symptomatic. The system can not only provide sentinel surveillance and other public health activities, but can facilitate research in disciplines such as immunology, virology, epidemiology, affective and cognitive neurobiology and health psychology. The aim and scope of this paper is to, within context, describe both the rationale and functional components and operation of this system in a variety of settings. The objective of the paper is to explicate both the operational characteristics of this approach and the multiple applications it may have in the disciplines identified above as well as primary health care and non-medical applications.

Immunotherapy (excluding checkpoint inhibitors) for stage I to III non-small cell lung cancer treated with surgery or radiotherapy with curative intent.

Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. This is an update of a Cochrane Review first published in 2017 and it includes two new randomised controlled trials (RCTs). To assess the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) among people with localised NSCLC of stages I to III who received curative intent ofradiotherapy or surgery. We searched the following databases (from inception to 19 May 2021): CENTRAL, MEDLINE, Embase, CINAHL, and five trial registers. We also searched conference proceedings and reference lists of included trials. We included RCTs conducted in adults (≥ 18 years) diagnosed with NSCLC stage I to III after surgical resection, and those with unresectable locally advanced stage III NSCLC receiving radiotherapy with curative intent. We included participants who underwent primary surgical treatment, postoperative radiotherapy or chemoradiotherapy if the same strategy was provided for both intervention and control groups. Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, using hazard ratios (HRs). We used risk ratios (RRs) for dichotomous data, and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we combined data by applying random-effects models. We included 11 RCTs involving 5128 participants (this included 2 new trials with 188 participants since the last search dated 20 January 2017). Participants who underwent surgical resection or received curative radiotherapy were randomised to either an immunotherapy group or a control group. The immunological interventions were active immunotherapy Bacillus Calmette-Guérin (BCG) adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell/cytokine-induced killer (DC/CIK), antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25), and targeted natural killer (NK) cells. Seven trials were at high risk of bias for at least one of the risk of bias domains. Three trials were at low risk of bias across all domains and one small trial was at unclear risk of bias as it provided insufficient information. We included data from nine of the 11 trials in the meta-analyses involving 4863participants. There was no evidence of a difference between the immunotherapy agents and the controls on any of the following outcomes: overall survival (HR 0.94, 95% CI 0.84to 1.05; P = 0.27; 4 trials, 3848 participants; high-quality evidence), progression-free survival (HR 0.94, 95% CI 0.86to 1.03; P = 0.19; moderate-quality evidence), adverse events (RR 1.12, 95% CI 0.97 to 1.28; P = 0.11; 4 trials, 4126 evaluated participants; low-quality evidence), and severe adverse events (RR 1.14, 95% CI 0.92to 1.40; 6 trials, 4546 evaluated participants; low-quality evidence). Survival rates at different time points showed no evidence of a difference between immunotherapy agents and the controls. Survival rate at 1-year follow-up (RR 1.02, 95% CI 0.96 to 1.08; I2 = 57%; 7 trials, 4420 participants; low-quality evidence), 2-year follow-up (RR 1.02, 95% CI 0.93 to 1.12; 7 trials, 4420 participants; moderate-quality evidence), 3-year follow-up (RR 0.99, 95% CI 0.90 to 1.09; 7 trials, 4420 participants; I2 = 22%; moderate-quality evidence) and at 5-year follow-up (RR 0.98, 95% CI 0.86 to 1.12; I2 = 0%; 7 trials, 4389 participants; moderate-quality evidence). Only one trial reported overall response rates. Two trials provided health-related quality of life results with contradicting results. AUTHORS' CONCLUSIONS: Based on this updated review, the current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for people with localised NSCLC (stages I to III). Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights into the role of immunotherapy for people with stages I to III NSCLC.

Cytokines and Chemokines in HBV Infection.

Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.

631 CLINICAL APPLICATION VALUE OF THE SYSTEMIC-IMMUNE-INFLAMMATION-INDEX FOR PREDICTING SURVIVAL IN PATIENTS WITH ESOPHAGEAL SQUAMOUS CELL CARCINOMA UNDERGOING CHEMORADIOTHERAPY OR RADIOTHERAPY

Abstract The systemic immune-inflammation index(SII), a prognostic index integrating neutrophils, platelets and lymphocytes, has been shown to have predictive value for several common cancers. The study aim was to explore the clinical application value of the SII for prognosis of patients with esophageal squamous-cell carcinoma (ESCC) treated with radical chemoradiotherapy (CRT) or radiotherapy (RT). Methods Overall, 180 patients with ESCC who received radiotherapy with or without chemotherapy, from March 20, 2012 to December 25, 2017 were retrospectively analyzed. Based on serum measurements before/after/during treatment, the SII at ESCC was calculated by multiplying the sera absolute neutrophil and platelet counts, and then, divided by the absolute lymphocyte count. The Kaplan–Meier method and Cox proportional regression models were used to analyze the relationship between SII at different time points, the ratio of before and after radiotherapy and overall survival (OS). Results The area under ROC-curve of Ratio of SII before and after radiotherapy(RT-pre/Post-SII) was 0.635. The AUC of SII-values before, during and after radiotherapy was 0.618, 0.624 and 0.453, respectively. The cutoff-value of RT-pre/Post-SII was 0.498, and the patients were divided into low RT-pre/Post-SII group(&amp;lt;0.498) and high RT-pre/Post-SII group(≥0.498). RT-pre/Post-SII was related to tumor-length, KPS and severe thrombocytopenia in ESCC patients(P &amp;lt; 0.05). The median-OS in the high and low RT-pre/Post-SII group were 909 days, and 466 days, respectively. Multivariate analysis showed that KPS(P = 0.045), lymphatic-metastasis(P = 0.032), Mid-RT SII(P &amp;lt; 0.001) and RT-pre/Post-SII(P = 0.003) was independent prognostic factors affecting the prognosis of patients in ESCC treated with RT/CRT. Conclusion The calculation of SII value is simple, reliable and repeatable and can improve the accuracy of a patient’s prognosis. ESCC patients treated with RT or CRT with high SII before, and during radiotherapy are most likely to benefit from early anti-inflammatory or immunotherapy before and during radiotherapy, while immunological intervention for SII after radiotherapy is of little significance. Confirmation of these results by a large-sample prospective study is desirable.