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Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while late-stage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies.

[This corrects the article DOI: 10.3389/fimmu.2023.1152035.].

Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future.

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

Conjugation of a vaccine adjuvant to an antigen enhances anti-tumor immune responses. Direct chemical conjugation, however, may limit their processing by the antigen-presenting cell for immune stimulation. To test this hypothesis, antigen-adjuvant conjugates were designed to be cleaved by an intracellular trigger to release antigen and adjuvant from each other. The different reductive environment inside and outside antigen-presenting cells was used as a trigger for targeted intracellular release. Two redox-responsive disulphide linkers were used to conjugate the model antigen ovalbumin to CpG. In vitro stability assays with the reductant glutathione showed that one conjugate (SS) was cleaved by glutathione concentrations of the extra- and intracellular compartments. A second conjugate (HYN-SS) was only cleaved at the higher intracellular glutathione concentration. In vitro cell culture studies showed that high T cell responses were generated by the HYN-SS and the stable conjugate HYN. The SS conjugate induced a lower T cell response similar to a mixture of CpG and ovalbumin. An in vivo therapeutic tumor trial demonstrated a superior survival rate of 9/10 for mice vaccinated with HYN-SS conjugate compared to HYN (6/10), SS (2/10), and the mixture (2/10). This intracellular cleavable conjugation strategy represents a promising approach to improve cancer immunotherapy of soluble vaccines. Conjugation of a vaccine adjuvant to an antigen enhances anti-tumor immune responses. Kramer et al. show that an intracellular cleavable antigen-adjuvant conjugate induces a superior anti-cancer immune response compared to a stable conjugate. This cleavable conjugation strategy represents a promising approach to improve cancer immunotherapy.

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using alpha 7-nicotinic acetylcholine receptor ( alpha 7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of alpha 7-nAChR modulators on innate immune cells.

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using [alpha]7-nicotinic acetylcholine receptor ([alpha]7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of [alpha]7-nAChR modulators on innate immune cells.

Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. Assessment of the full range of evidence generated to date to understand the characteristics of the antibody response, its dynamics over time, its determinants and the immunity it confers will have a range of clinical and policy implications for this novel pathogen. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020. Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence (MetaQAT) tool, with resolution of disagreements by consensus. Findings were narratively synthesised. 150 papers were included. Most studies (113 or 75%) were observational in design, were based wholly or primarily on data from hospitalised patients (108, 72%) and had important methodological limitations. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, up to around three months from disease onset, but the picture regarding correlates of the antibody response was inconsistent. IgM was consistently detected before IgG in included studies, peaking at weeks two to five and declining over a further three to five weeks post-symptom onset depending on the patient group; IgG peaked around weeks three to seven post-symptom onset then plateaued, generally persisting for at least eight weeks. Neutralising antibodies were detectable within seven to 15 days following disease onset, with levels increasing until days 14-22 before levelling and then decreasing, but titres were lower in those with asymptomatic or clinically mild disease. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross-reactivity but limited cross-neutralisation with other human coronaviridae was reported. Evidence for protective immunity in vivo was limited to small, short-term animal studies, showing promising initial results in the immediate recovery phase. Literature on antibody responses to SARS-CoV-2 is of variable quality with considerable heterogeneity of methods, study participants, outcomes measured and assays used. Although acute phase antibody dynamics are well described, longer-term patterns are much less well evidenced. Comprehensive assessment of the role of demographic characteristics and disease severity on antibody responses is needed. Initial findings of low neutralising antibody titres and possible waning of titres over time may have implications for sero-surveillance and disease control policy, although further evidence is needed. The detection of potent neutralising antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines. Due to limitations with the existing evidence base, large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.

The oxygenation of the Earth's deep oceans is often thought to have triggered the evolution of simple animals. A review article proposes that instead, the evolution of animal life set off a series of biogeochemical feedbacks that promoted the oxygenation of the deep sea. The Neoproterozoic era (about 1,000 to 542 million years ago) was a time of turbulent environmental change. Large fluctuations in the carbon cycle were associated with at least two severe — possible Snowball Earth — glaciations. There were also massive changes in the redox state of the oceans, culminating in the oxygenation of much of the deep oceans. Amid this environmental change, increasingly complex life forms evolved. The traditional view is that a rise in atmospheric oxygen concentrations led to the oxygenation of the ocean, thus triggering the evolution of animals. We argue instead that the evolution of increasingly complex eukaryotes, including the first animals, could have oxygenated the ocean without requiring an increase in atmospheric oxygen. We propose that large eukaryotic particles sank quickly through the water column and reduced the consumption of oxygen in the surface waters. Combined with the advent of benthic filter feeding, this shifted oxygen demand away from the surface to greater depths and into sediments, allowing oxygen to reach deeper waters. The decline in bottom-water anoxia would hinder the release of phosphorus from sediments, potentially triggering a potent positive feedback: phosphorus removal from the ocean reduced global productivity and ocean-wide oxygen demand, resulting in oxygenation of the deep ocean. That, in turn, would have further reinforced eukaryote evolution, phosphorus removal and ocean oxygenation.

Insufficient growth during childhood is associated with poor health outcomes and an increased risk of death. Between 2000 and 2015, nearly all African countries demonstrated improvements for children under 5 years old for stunting, wasting, and underweight, the core components of child growth failure. Here we show that striking subnational heterogeneity in levels and trends of child growth remains. If current rates of progress are sustained, many areas of Africa will meet the World Health Organization Global Targets 2025 to improve maternal, infant and young child nutrition, but high levels of growth failure will persist across the Sahel. At these rates, much, if not all of the continent will fail to meet the Sustainable Development Goal target—to end malnutrition by 2030. Geospatial estimates of child growth failure provide a baseline for measuring progress as well as a precision public health platform to target interventions to those populations with the greatest need, in order to reduce health disparities and accelerate progress. Geospatial estimates of child growth failure in Africa provide a baseline for measuring progress and a precision public health platform to target interventions to those populations with the greatest need. Mapping Africa's path to prosperity The UN's Sustainable Development Goals set a range of targets to improve global health and prosperity. Their success will rely on high-quality data to assess current progress and needs on a local scale. Simon Hay and colleagues study data gathered at the finest spatial scale yet of child growth and educational attainment across 51 African countries. The data show the spatiotemporal progression of these measures between 2000 and 2015 and reveal geographical inequalities. The authors use Bayesian-model-based geospatial mapping to estimate the prevalence of multiple outcomes related to child growth failure and educational inequality on a 5 kilometre by 5 kilometre scale, enabling them to estimate where various targets related to nutrition and educational attainment are more or less likely to be met.