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Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. ClinicalTrials.gov NCT02019355. Not applicable (investigator-initiated clinical trial).

SARS-CoV-2 has caused millions of deaths, and, since Aug 11, 2020, 20 intramuscular COVID-19 vaccines have been approved for use. We aimed to evaluate the safety and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults without COVID-19 from China. This was a randomised, single-centre, open-label, phase 1 trial done in Zhongnan Hospital (Wuhan, China), to evaluate the safety and immunogenicity of the Ad5-nCoV vaccine by aerosol inhalation in adults (≥18 years) seronegative for SARS-CoV-2. Breastfeeding or pregnant women and people with major chronic illnesses or history of allergies were excluded. Participants were enrolled and randomly assigned (1:1:1:1:1) into five groups to be vaccinated via intramuscular injection, aerosol inhalation, or both. Randomisation was stratified by sex and age (18–55 years or ≥56 years) using computer-generated randomisation sequences (block sizes of five). Only laboratory staff were masked to group assignment. The participants in the two aerosol groups received an initial high dose (2 × 1010 viral particles; HDmu group) or low dose (1 × 1010 viral particles; LDmu group) of Ad5-nCoV vaccine on day 0, followed by a booster on day 28. The mixed vaccination group received an initial intramuscular (5 × 1010 viral particles) vaccine on day 0, followed by an aerosolised booster (2 × 1010 viral particles) vaccine on day 28 (MIX group). The intramuscular groups received one dose (5 × 1010 viral particles; 1Dim group) or two doses (10 × 1010 viral particles; 2Dim group) of Ad5-nCoV on day 0. The primary safety outcome was adverse events 7 days after each vaccination, and the primary immunogenicity outcome was anti-SARS-CoV-2 spike receptor IgG antibody and SARS-CoV-2 neutralising antibody geometric mean titres at day 28 after last vaccination. This trial is registered with ClinicalTrials.gov, number NCT04552366. Between Sept 28, 2020, and Sept 30, 2020, 230 individuals were screened for inclusion, of whom 130 (56%) participants were enrolled into the trial and randomly assigned into one of the five groups (26 participants per group). Within 7 days after vaccination, adverse events occurred in 18 (69%) in the HDmu group, 19 (73%) in the LDmu group, 19 (73%) in the MIX group, 19 (73%) in the 1Dim group, and 15 (58%) in the 2Dim group. The most common adverse events reported 7 days after the first or booster vaccine were fever (62 [48%] of 130 participants), fatigue (40 [31%] participants), and headache (46 [35%] participants). More adverse events were reported in participants who received intramuscular vaccination, including participants in the MIX group (49 [63%] of 78 participants), than those who received aerosol vaccine (13 [25%] of 52 participants) after the first vaccine vaccination. No serious adverse events were noted within 56 days after the first vaccine. At days 28 after last vaccination, geometric mean titres of SARS-CoV-2 neutralising antibody was 107 (95% CI 47–245) in the HDmu group, 105 (47–232) in the LDmu group, 396 (207–758) in the MIX group, 95 (61–147) in the 1Dim group, and 180 (113–288) in the 2Dim group. The geometric mean concentrations of receptor binding domain-binding IgG was 261 EU/mL (95% CI 121–563) in the HDmu group, 289 EU/mL (138–606) in the LDmu group, 2013 EU/mL (1180–3435) in the MIX group, 915 EU/mL (588–1423) in the 1Dim group, and 1190 EU/mL (776–1824) in the 2Dim group. Aerosolised Ad5-nCoV is well tolerated, and two doses of aerosolised Ad5-nCoV elicited neutralising antibody responses, similar to one dose of intramuscular injection. An aerosolised booster vaccination at 28 days after first intramuscular injection induced strong IgG and neutralising antibody responses. The efficacy and cost-effectiveness of aerosol vaccination should be evaluated in future studies. National Key Research and Development Programme of China and National Science and Technology Major Project. For the Chinese translation of the Summary see Supplementary Material.

Key Points Interleukin-10 (IL-10) is not a cell type-specific cytokine, but instead it is broadly expressed by many immune cells. Several layers of regulation regulate IL-10 production, including changes in the chromatin structure, enhancement or silencing of IL10 transcription and post-transcriptional regulatory mechanisms. Many of the molecular events leading to IL10 expression are similar and common to various IL-10-producing immune cells, but cell type-specific signals also exist. Induction of IL-10 often occurs together with pro-inflammatory cytokines, although pathways that induce IL-10 may actually negatively regulate these pro-inflammatory cytokines. Understanding the specific molecular events that regulate the expression of IL-10 will be important for the design of new strategies of immune intervention. The anti-inflammatory cytokine interleukin-10 (IL-10) has a central role in limiting inflammatory responses to protect against excessive tissue damage. Recent evidence suggests that many types of immune cell can produce IL-10, but how is its transcription regulated in these different cell types? Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.

Hosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses. Toxoplasmosis: Insights into immunity Researchers are extensively studying immune responses to the single-celled parasite Toxoplasma gondii , which infects around one-third of humans, often harmlessly, but can cause life-threatening toxoplasmosis infections in patients with weakened immune systems. Masahiro Yamamoto and Miwa Sasai at Osaka University in Japan review recent advances in understanding the interactions between the immune system and the parasite. They consider non-specific ‘innate’ immune responses and also the ‘acquired’ responses that target specific parts of the parasite, referred to as antigens. Methods that selectively switch off genes in mice are revealing details presumed to also be relevant for humans. Significant molecules, molecular signaling pathways and immune-regulating processes are being identified. Recent studies suggest cell-autonomous immunity, the ability of host cells to defend themselves against attack, plays a significant role in fighting Toxoplasma gondii infection.

Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

At the current time, the field of vaccinology remains empirical in many respects. Vaccine development, vaccine immunogenicity, and vaccine efficacy have, for the most part, historically been driven by an empiric “isolate-inactivate-inject” paradigm. In turn, a population-level public health paradigm of “the same dose for everyone for every disease” model has been the normative thinking in regard to prevention of vaccine-preventable infectious diseases. In addition, up until recently, no vaccines had been designed specifically to overcome the immunosenescence of aging, consistent with a post-WWII mentality of developing vaccines and vaccine programs for children. It is now recognized that the current lack of knowledge concerning how immune responses to vaccines are generated is a critical barrier to understanding poor vaccine responses in the elderly and in immunoimmaturity, discovery of new correlates of vaccine immunogenicity (vaccine response biomarkers), and a directed approach to new vaccine development. The new fields of vaccinomics and adversomics provide models that permit global profiling of the innate, humoral, and cellular immune responses integrated at a systems biology level. This has advanced the science beyond that of reductionist scientific approaches by revealing novel interactions between and within the immune system and other biological systems (beyond transcriptional level), which are critical to developing “downstream” adaptive humoral and cellular responses to infectious pathogens and vaccines. Others have applied systems level approaches to the study of antibody responses (a.k.a. “systems serology”), [1] high-dimensional cell subset immunophenotyping through CyTOF, [2,3] and vaccine induced metabolic changes [4]. In turn, this knowledge is being utilized to better understand the following: identifying who is at risk for which infections; the level of risk that exists regarding poor immunogenicity and/or serious adverse events; and the type or dose of vaccine needed to fully protect an individual. In toto, such approaches allow for a personalized approach to the practice of vaccinology, analogous to the substantial inroads that individualized medicine is playing in other fields of human health and medicine. Herein we briefly review the field of vaccinomics, adversomics, and personalized vaccinology.

New influenza vaccines eliciting more effective protection are needed, particularly for the elderly who paid a large and disproportional toll of hospitalization and dead during seasonal influenza epidemics. Low (≤15 μg/strain) doses of a new plant-derived virus-like-particle (VLP) vaccine candidate have been shown to induce humoral and cellular responses against both homologous and heterologous strains in healthy adults 18-64 years of age. The two clinical trials reported here addressed the safety and immunogenicity of higher doses (≥15 μg/strain) of quadrivalent VLP candidate vaccine on 18-49 years old and ≥50 years old subjects. We also investigated the impact of alum on the immunogenicity induced by lower doses of the vaccine candidate. In the first Phase II trial reported here (NCT02233816), 18-49 year old subjects received 15, 30 or 60 μg/strain of a hemagglutinin-bearing quadrivalent virus-like particle (QVLP) vaccine or placebo. In the second trial (NCT02236052), ≥50 years old subjects received QVLP as above or placebo with additional groups receiving 7.5 or 15 μg/strain with alum. Along with safety recording, the humoral and cell-mediated immune responses were analyzed. Local and systemic side-effects were similar to those reported previously. The QVLP vaccine induced significant homologous and heterologous antibody responses at the two higher doses, the addition of alum having little-to-no effect. Serologic outcomes tended to be lower in ≥50 years old subjects previously vaccinated. The candidate vaccine also consistently elicited both homologous and heterologous antigen-specific CD4+ T cells characterized by their production of interferon-gamma (IFN-γ), interleukine-2 (IL-2) and/or tumor-necrosis factor alpha (TNF-α) upon ex vivo antigenic restimulation. Overall, the 30 μg dose produced the most consistent humoral and cellular responses in both 18-49 and ≥50 years old subjects, strongly supporting the clinical development of this candidate vaccine. That particular dose was chosen to test in the ongoing Phase III clinical trial.

Key Points The adenosinergic pathway encompasses ectonucleotidases (CD39 and CD73) and adenosine receptors (A1R, A2AR, A2BR and A3R) that participate in the generation and signalling of adenosine in the tumour microenvironment (TME), respectively. Of the four adenosine receptors, the cyclic AMP (cAMP)-activating receptors A2AR and A2BR predominantly exert immunosuppressive functions in the TME. Molecules of this pathway are regulated by several immunogenic and genetic drivers. Of these, hypoxia and transforming growth factor-β (TGFβ) represent the key drivers of the adenosinergic pathway. Within a tumour niche, adenosinergic molecules are expressed by tumour cells, stromal cells and immune cells, and their critical point of action is not yet fully understood. Adenosine, through activation of cAMP, can directly regulate tumour proliferation, survival, adhesion and migration. In immune cells, adenosine molecules greatly hamper vital immune effector cell functions and may be involved in mediating T cell exhaustion. Novel antibodies and small molecules targeted to members of the adenosinergic pathway are now reaching clinical trials in patients with advanced cancer and may be combined with standard-of-care therapies and novel immunotherapies. The adenosinergic pathway is a major immunosuppressive mechanism in the tumour microenvironment. In this Review, Vijayan et al . discuss how targeting components involved in the generation and downstream signalling of extracellular adenosine represents an attractive novel cancer therapy. Despite the success of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments (known as innate resistance). In addition, one-third of patients relapse after initial response (known as adaptive resistance), which suggests that multiple non-redundant immunosuppressive mechanisms coexist within the tumour microenvironment. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. Preclinical studies in mice with adenosine receptor antagonists and antibodies have reported favourable antitumour immune responses with some definition of the mechanism of action. Currently, agents targeting the adenosinergic pathway are undergoing first-in-human clinical trials as single agents and in combination with anti-PD1 or anti-PDL1 therapies. In this Review, we describe the complex interplay of adenosine and adenosine receptors in the development of primary tumours and metastases and discuss the merits of targeting one or more components that compose the adenosinergic pathway. We also review the early clinical data relating to therapeutic agents inhibiting the adenosinergic pathway.

Glioblastoma is highly enriched with macrophages, and osteopontin (OPN) expression levels correlate with glioma grade and the degree of macrophage infiltration; thus, we studied whether OPN plays a crucial role in immune modulation. Quantitative PCR, immunoblotting, and ELISA were used to determine OPN expression. Knockdown of OPN was achieved using complementary siRNA, shRNA, and CRISPR/Cas9 techniques, followed by a series of in vitro functional migration and immunological assays. OPN gene-deficient mice were used to examine the roles of non-tumor-derived OPN on survival of mice harboring intracranial gliomas. Patients with mesenchymal glioblastoma multiforme (GBM) show high OPN expression, a negative survival prognosticator. OPN is a potent chemokine for macrophages, and its blockade significantly impaired the ability of glioma cells to recruit macrophages. Integrin αvβ5 (ITGαvβ5) is highly expressed on glioblastoma-infiltrating macrophages and constitutes a major OPN receptor. OPN maintains the M2 macrophage gene signature and phenotype. Both tumor-derived and host-derived OPN were critical for glioma development. OPN deficiency in either innate immune or glioma cells resulted in a marked reduction in M2 macrophages and elevated T cell effector activity infiltrating the glioma. Furthermore, OPN deficiency in the glioma cells sensitized them to direct CD8+ T cell cytotoxicity. Systemic administration in mice of 4-1BB-OPN bispecific aptamers was efficacious, increasing median survival time by 68% (P < 0.05). OPN is thus an important chemokine for recruiting macrophages to glioblastoma, mediates crosstalk between tumor cells and the innate immune system, and has the potential to be exploited as a therapeutic target.

Social status is one of the strongest predictors of human disease risk and mortality, and it also influences Darwinian fitness in social mammals more generally. To understand the biological basis of these effects, we combined genomics with a social status manipulation in female rhesus macaques to investigate how status alters immune function. We demonstrate causal but largely plastic social status effects on immune cell proportions, cell type-specific gene expression levels, and the gene expression response to immune challenge. Further, we identify specific transcription factor signaling pathways that explain these differences, including low-status-associated polarization of the Toll-like receptor 4 signaling pathway toward a proinflammatory response. Our findings provide insight into the direct biological effects of social inequality on immune function, thus improving our understanding of social gradients in health.