Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer

BACKGROUND There is an intimate crosstalk between cancer formation,dissemination,treatment response and the host immune system,with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments.However,inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive.The release of damage associated molecular patterns(DAMPs)is indicative of immunogenic cell death and propagation of established immune responses.However,there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma(OAC)or by immune cells themselves.AIM To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer.METHODS We investigated the levels of immunogenic cell death-associated DAMPs,calreticulin(CRT)and HMGB1 using an OAC isogenic model of radioresistance.DAMP expression was also assessed directly using ex vivo cancer patient T cells(n=10)and within tumour biopsies(n=9)both pre and post-treatment with clinically relevant chemo(radio)therapeutics.RESULTS Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro.Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo-(radio)therapy,which was significantly higher in tumour tissue compared with peripheral blood.Patients with high expression of HMGB1 had a significantly better tumour regression grade(TRG 1-2)compared to low expressors.CONCLUSION In conclusion,OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors,which correlated with tumour regression grade and lymphatic invasion.It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018.A large amount of evidence supports the amyloid cascade hypothesis,which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles,and these aggregates lead to inflammation,synaptic impairment,neuronal loss,and thus to cognitive decline and behavioral abnormalities.The poor correlation found between cognitive decline and amyloid plaques,have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer’s disease.The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and,although amyloid-beta may initiate the cascade of events,tau impairment is likely the effector molecule of neurodegeneration.Recently,it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and,more importantly,that downregulation of tau partially reverses transcriptional perturbations.Despite mounting evidence points to an interplay between amyloid-beta and tau,some factors could independently affect both pathologies.Thus,the dual pathway hypothesis,which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed.Among others,the immune system seems to be strongly involved in amyloid-beta and tau pathologies.Other factors,as the apolipoprotein Eε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation.Interestingly,amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials.Likewise,it has been shown that tau-immunotherapy also reduces amyloid-beta levels.Thus,even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy,combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer’s disease.

Montanide ISA-720 and Naloxone in HBsAg Vaccine Formulation:Cytokine Profiling and Monitoring of Long-Lasting Humoral Immune Responses

Objective This study aimed to investigate the effects of Montanide ISA-720 and Naloxone(NLX)in Hepatitis B surface antigen(HBsAg)vaccine formulation on cytokine and long-lasting antibody responses.Methods First,the HBsAg was formulated in Montanide ISA-720 adjuvant and Naloxone at 5 and 10mg/kg.The experimental mice were immunized three times at a 2-week interval,and then IL-4,IL-2,TNF-α,and IFN-γcytokines;long-lasting IgG antibody responses 220 days after the last shot;and IgG1/IgG2a isotypes were assessed by ELISA.Results The HBsAg-Alum group exhibited the highest IL-4 cytokine response among the experimental groups,whereas NLX in HBsAg-MON720 vaccine formulation did not affect cytokine responses.In addition,NLX in Alum-based vaccine suppressed IL-4 cytokine response and increased the IL-2/IL-4 cytokine ratio.Moreover,HBsAg-MON720 was more potent than HBsAg-Alum in the induction of antibody responses,and NLX in Alum-and MON720-based vaccines induced long-lasting antibody responses.Conclusion NLX in Alum-based vaccine decreased IL-4 cytokine response,increased IL-2/IL-4 cytokine ratio,and improved long-lasting humoral immune responses in both vaccine formulations.Therefore,the adjuvant activity of NLX in the vaccine formulation depends on the type of adjuvant and the nature of the antigen in the vaccine formulation.

Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy

Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune diseases.In most cases,the presence of TLS correlates with active immune responses.Because of their proximity to pathological loci,TLS are an intriguing target for the manipulation of immune responses.For several years,it has become clear that lymphotoxin(LT)signalling plays critical roles in lymphoid tissue organogenesis and maintenance.In the current review,we will discuss the role of LT signalling in the development of TLS.With a focus on cancers and autoimmune diseases,we will highlight the correlations between TLS and disease progression.We will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.