Cell Immune Surveillance Research Articles

Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells

Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain–containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte–macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.

Non-specific inflammatory bowel disease and the risk of tumour growth

Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn’s disease (Lesniowski-Crohn’s, ChL-C, CD), is a chronic and recurrent inflammatory condition of the gastrointestinal tract with multifactorial causes. Both types of IBD are characterized by chronic inflammation with periods of remission and exacerbation. An increasing number of studies have recently shown that chronic inflammation plays an important role in the carcinogenesis of colorectal cancer (CRC), generating suitable microenvironments for the formation and progression of the disease. The main factors are chronic inflammation and the scope and duration of the disease. The pro-inflammatory interleukins IL-13, IL-8 and TNF-α play an important role in tumorigenesis. It is further emphasized that reactive oxygen species (ROS) and reactive nitrogen species produced by inflammatory cells may interact with key genes involved in carcinogenic pathways such as TP53. Carcinogenesis in IBD involves proteins determined by the genes DLG5, OCTN and NOD2. Immunosuppressive drugs such as thiopurines and methotrexate may play a role in extra-intestinal tumour development by impairing the immune system and surveillance of tumour cells or by inducing DNA damage. Recognition of neoplastic changes associated with IBD is difficult due to the heterogeneity of the endoscopic image and variation in the diagnosis depending on the observer. Therefore surveillance of IBD patients by a multidisciplinary team is essential for early detection of the neoplastic process.

Cutaneous immune system: Age specificities

<p>The review is dedicated to the modern concepts in understanding the age-related changes of skin protective functions, with an emphasis on the impairments in interaction between the immune cells of innate and acquired immunity, resulting in a decrease in antigen-specific T cell immune surveillance in the skin. We discuss the various defects of T cells and their environment as well as focus on the issue of possible correction of T-reg and other cells activity in the skin which would increase the level of immune surveillance in elderly persons and reduce the risk of malignant neoplasms or skin infections developing.</p>

Identification of Biomarkers for Tubular Injury and Interstitial Fibrosis in Chronic Kidney Disease

In chronic kidney disease (CKD), progressive nephron loss causes tubulointerstitial fibrosis and progressive tubular injury. Recent identification of the major cell populations of myofibroblast precursors in the kidney has enabled us to dissect the fibrogenic process after tubular injury. Kidney pericytes are a possible precursor of myofibroblasts, and may be promising targets for treating fibrogenesis. Our recent studies have shown that pericytes activate Toll-like receptor (TLR) 2/4- and myeloid differentiation primary response 88 (MyD88)-dependent proinflammatory signaling in response to renal tubular injury. We also found active roles of inflammasomes in kidney pericytes, leading to interleukin (IL)-1β and IL-18 secretion. Genetic ablation of MyD88 in pericytes, or pharmacological inhibition of MyD88 signaling by an IL-1 receptor-associated kinase 4 (IRAK4) inhibitor, halted interstitial fibrosis after renal tubular injury. Our data indicate that pericytes not only contribute to interstitial fibrosis by aberrant wound-healing responses, but also serve as innate immune surveillance cells that regulate the inflammatory process, exacerbating tubular injury by the release of cytokines and chemokines. On the other hand, our recent study using a microarray analysis aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage in patients with CKD. The results indicated that 5 genes were up-regulated in the kidney of CKD patients, and that their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury. These findings provide important information for the development of diagnostic tools and therapeutic agents for predicting and preventing progressive renal disease.

The effect of upper-respiratory viral infection on leukocyte surveillance of the brain

Peripheral infections exacerbate symptoms of many neurological diseases, including the most common autoimmune demyelinating disease of the central nervous system (CNS), multiple sclerosis (MS). We hypothesized that upper-respiratory viral infection induces glial activation and results in immune cell trafficking to the CNS, which may be detrimental to MS patients. To test this hypothesis we inoculated C57BL/6 mice with saline or influenza A virus (Puerto Rico/8/34; PR8). Glial activation and chemokine expression was evaluated by RNA-seq at days 0, 4, and 8 p.i.. Immune cell surveillance over the course of infection was assessed by flow cytometry. Chemokine levels in the cerebrospinal fluid of MS patients in remission and relapse were measured by luminex. Influenza infection caused transcriptomic changes to the cerebellum and spinal cord which was consistent with and glial activation and induced a predominantly A1 reactive astrocyte gene expression profile. Infection increased the expression of Ccl6 and Cxcl5 in the cerebellum and modulated expression of Ccl17, Ccl25, Ccl28, Ccl27a and Cx3cl1 in both the cerebellum and spinal cord. Flow cytometry analysis indicated that infection increased immune surveillance of the brain by monocytes and neutrophils as well as altered the profile of B-cells in the CNS. Finally, we found that CXCL5 was increased in the CSF of patients during relapse compared with those in remission.

Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer

ABSTRACTThe tumor infiltration of immune cells in solid cancers can profoundly influence host antitumor responses. In recent years, immunotherapeutic regimens, that target immune checkpoints, demonstrated significant antitumor response by increasing intra-tumoral immune cell populations, including CD8+ effector T cells. However, administration of such immune checkpoint inhibitors is largely inefficacious in inducing immunogenicity and treating breast cancer. Currently, there is a great need to better understand cell autonomous mechanisms of immune evasion in breast cancer to identify upstream therapeutic targets that increase the efficacy of immunotherapy. Here we show that Crk, an SH2 and SH3 domain-containing adaptor protein implicated in focal adhesion signaling, cell migration, and invasion, and frequently up-regulated in human cancers, has an important role in regulating the tumor immune microenvironment. Using a murine 4T1 breast adenocarcinoma model of spontaneous metastasis in immune-competent BALB/C mice, we show that genetic ablation of Crk by CRISPR-Cas9 leads to enhanced anti-tumor immune cell populations, cytotoxic effector and immune surveillance cytokines in primary tumor. Pathologically, this leads to a significant reduction in tumor growth and lung metastasis. Mechanistically, Crk KO suppresses EMT and PD-L1 expression on tumor cells and acts additively with anti-PD1 therapy to suppress tumor growth and metastasis outcomes. Taken together, these data reveal a previously un-described function of Crk adaptor protein expression in tumor cells for cell autonomous regulation of tumor immune microenvironment.

Re-balance of memory T cell subsets in peripheral blood from patients with CML after TKI treatment.

T cell immune surveillance is considered an important host protection process for inhibiting carcinogenesis. The full capacity of T cell immune surveillance is dependent on T cell homeostasis, particularly for central memory T (TCM) cells and stem cell memory T (TSCM) cells. In this study, distribution of T cell subsets in peripheral blood from 12 patients with chronic myeloid leukemia (CML) and 12 cases with CML in complete remission (CR) was analyzed using a multicolor flow cytometer, and 16 samples from healthy individuals (HIs) served as control. The proportion of CD8+ TSCM and CD4+ and CD8+ TCM cells were lower, while CD4+ effector memory T (TEM) cells and CD4+ and CD8+ terminal effector T (TEF) cells were higher in CML patients compared with HIs. Moreover, the proportion of CD8+CD28- T cells, which were found to have the immune suppressive function, increased in the naive T (TN) cell and TCM subsets in CML patients compared with HIs. Our study reveals that elimination of leukemia cells by treating with tyrosine kinase inhibitors (TKIs) restores the memory T cell distribution from a skewed pattern in CML patients who are under leukemia burden, indicating that leukemia-specific immune responses mediated by T cells might be induced and maintained in CML patients, however, these responsive T cells might gradually become exhausted due to the continued existence of leukemia cells and their environment; therefore, T cell activation using a different approach remains a key point for enhancing global T cell immunity in CML patients, even for those with CR status.

Abstract P387: Depletion of Perivascular Macrophages in the Brain Delays Blood Pressure Elevation in Angiotensin II-salt Hypertensive Rats

Objectives: Perivascular macrophages in the cerebrospinal fluid (CSF) are immune surveillance cells in the brain. Increase in angiotensin II (Ang II) in the periphery gradually produces neurogenic hypertension which is associated with brain inflammation. However, little is known on the role of perivascular macrophages in the CSF on neurogenic hypertension. We hypothesized that perivascular macrophages in the CSF have an important role in the development of neurogenic hypertension by relaying and amplifying excess peripheral Ang II signals to brain parenchyma. Methods: Sprague-Dawley rats had surgery to instrument radio telemetric pressure transducers to abdominal aorta. Following a one-week recovery period, the rats had surgery to implant either saline or Ang II filled osmotic minipump subcutaneously and received intracerebroventricular (icv) injection of either control liposome or clodronate liposome. The clodronate liposome is a drug that selectively induces apoptosis to macrophages which have liposome phagocytic activity. After the surgery, all rats were provided high-salt diet (2.0% NaCl). Blood pressure of rats was recorded three times a week for 2 weeks. Different set of rats had hexamethonium challenge test to evaluate sympathetic tone in 7 or 9 day after initiation of the infusions. Results: Rats that received Ang II infusion with control icv (n=7) gradually increased mean arterial pressure (MAP) compared with rats that received saline infusion (n=5) and reached significant increase in 6 days after the initiation of infusions. Rats that received Ang II infusion with clodronate icv (n=6) had delayed increase in MAP and reached significant increase in 10 days and had significantly lower MAP (91±4 mmHg) compared with rats that received Ang II infusion with control icv (111±4 mmHg) in day 8. Peak depressor response to hexamethonium was increased only in rats that received Ang II infusion with control icv when compared with saline infused rats examined in 7 or 9 days after initiation of the infusions. Conclusion: Perivascular macrophages in the CSF may have important role in the development of angiotensin II-salt neurogenic hypertension.

OR11 Low content of activating killer immunoglobulin-like receptors predispose to hematological malignancies

Aim Natural killer (NK) cells are critical in surveillance against viral infections and malignancies. Central to the regulation of NK cells is incredible diversity of activating and inhibitory Killer cell Ig-like receptors (KIR) that manifests in differential NK cell responses among different individuals. This diversity together with variability in KIR-HLA class I ligand is expected to modify the susceptibility to hematological malignancies. Here, we addressed this effect by studying comprehensive KIR gene profile in a Canadian cohort of myelogenous and lymphocytic leukemias. Methods A retrospective cohort of 837 subjects including patients of hematological malignancies (n = 377; myelogenous leukemias, n = 215; lymphocytic leukemia, n = 152) and healthy individuals (n = 460) were recruited. The KIR gene profiles were obtained using next generation sequencing and HLA class I genotypes were obtained by Luminex-based rSSO. Different case-control cohorts were tested for KIR and HLA-class I distribution (gene content, haplotypes and KIR-ligand combinations) by univariate and multivariate analysis. Results Lower content of activating KIR genes strongly correlated with increased incidences of hematological malignancies in a dose-dependent manner. The activating KIR content of ⩾3 activating KIR (=0.018, OR = 0.72, 95% CI = 0.55—0.95), ⩾4 activaing KIRs ( P = 0.004, OR = 0.66, 95% CI = 0.50-0.87) and ⩾5 activating KIRs ( P = 0.001, OR = 0.58, 95% CI = 0.42-0.81) were observed significantly more frequent in healthy controls as compared to patients of Hematological Malignancies. The strongest association was observed with lymphocytic leukemia while a trend of similar but non-significant association was observed with myelogenous leukemia. Conclusions Patients of hematological malignancies in general and that of lymphocytic leukemia in particular have low content of activating KIR genes. The findings suggest that low activating KIR gene content could lead to a deficient NK cell mediated immune surveillance of cancer cells.

PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome.

Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.

Implication of chemo-resistant memory T cells for immune surveillance in patients with sarcoma receiving chemotherapy.

Chemotherapy has improved the prognosis of patients with sarcomas. However, it may suppress anti‐tumor immunity. Recently, we reported a novel CD8+ memory T cell population with a chemo‐resistance property, “young memory” T (TYM) cells. In this study, we investigated the proportion and function of TYM cells in peripheral blood of healthy donors and sarcoma patients who received chemotherapy and those who did not. The proportion of TYM cells was significantly decreased in patients compared with that in healthy donors. In healthy donors, anti‐EBV CTLs were induced using mixed lymphocyte peptide culture, from not only TYM cells but also TCM and TEM cells. No CTLs directed to tumor‐associated antigens were induced. In sarcoma patients who did not receive chemotherapy, in addition to anti‐EBV CTLs, CTLs directed to the tumor‐associated antigen PBF were induced from TYM, TCM and TEM cells. In sarcoma patients who received chemotherapy, EBV‐specific CTLs were induced from TYM cells but were hardly induced from TEM cells. Interestingly, CTLs directed to the anti‐tumor‐associated antigen PBF were induced from TYM cells but not from the TCM and TEM cells in sarcoma patients who received chemotherapy. The findings suggest that TYM cells are resistant to chemotherapy and can firstly recover from the nadir. TYM cells might be important for immunological memory, especially in sarcoma patients receiving chemotherapy.

Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer.

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 2779-83. ©2017 AACR.

Expression of MICA/b, a ligand for natural killer (NK) cell recognition, on human pancreatic adenocarcinoma and potential for NK intervention.

129 Background: Pancreatic cancer remains a leading cause of cancer-related mortality because of lack of means for early detection and notable refractoriness to standard chemotherapy in advanced stages of disease. Mobilization of the immune system is therefore an important option to explore. Natural Killer (NK) cells are potent effector cells in immune surveillance against cancer and offer a unique advantage because of expression of a C-type, lectin-like, type II transmembrane glycoprotein, NKG2D, on the cell surface. NKG2D is a receptor that specifically recognizes common stress-induced proteins such as MICA/B on tumor cells, targeting them for perforin/granzyme B-mediated destruction. The goal of this study is to examine if MICA/B is expressed on human pancreatic cancer cells, allowing the potential to direct immunotherapy against pancreatic cancer via NK cell therapy. Methods: This study was conducted under an IRB approved protocol. Pancreatic samples were taken from 121 patients with pancreatic ductal adenocarcinoma (PDA) and 103 cases of normal adjacent pancreatic tissues (NP) were included for comparison in a tissue microarray developed in the Tissue Core. All cases were stained for MICA/B AB using the Ventana automated immunostainer Discovery XT (Ventana,Tucson, AZ). Human pancreatic cell lines were also immunostained for MICA/B expression and tested for sensitivity to NK cell lysis in vitro. Results: A significant increase in MICA/B expression was observed during the progression from NP to PDA (p value < 0.0001) in pancreatic tumor tissues. Additionally, all pancreatic cell lines, including MiaPaca, Panc-1, and PCSC, express MICA/B and were readily lysed by NK cells. Conclusions: We report an increase in MICA/B expression during the progression of pancreatic ductal adenocarcinoma and MICA/B may represent a new immunotherapeutic target in pancreatic gastric carcinogenesis.

Long time behavior of a tumor-immune system competition model perturbed by environmental noise

This paper investigates the long time behavior of tumor cells evolution in a tumor-immune system competition model perturbed by environmental noise. Sufficient conditions for extinction, stochastic persistence, and strong persistence in the mean of tumor cells are derived by constructing Lyapunov functions. The study results show that environmental noise can accelerate the extinction of tumor cells under immune surveillance of effector cells, which means that noise is favorable for the extinction of tumor in this condition. Finally, numerical simulations are introduced to support our results.

Lung pericyte-like cells are functional interstitial immune sentinel cells.

Pericytes are perivascular PDGF receptor-β+ (PDGFRβ+) stromal cells required for vasculogenesis and maintenance of microvascular homeostasis in many organs. Because of their unique juxtaposition to microvascular endothelium, lung PDGFRβ+ cells are well situated to detect proinflammatory molecules released following epithelial injury and promote acute inflammatory responses. Thus we hypothesized that these cells represent an unrecognized immune surveillance or injury-sentinel interstitial cell. To evaluate this hypothesis, we isolated PDGFRβ+ cells from murine lung and demonstrated that they have characteristics consistent with a pericyte population (referred to as pericyte-like cells for simplicity hereafter). We showed that pericyte-like cells expressed functional Toll-like receptors and upregulated chemokine expression following exposure to bronchoalveolar lavage fluid (BALF) collected from mice with sterile lung injury. Interestingly, BALF from mice without lung injury also induced chemokine expression in pericyte-like cells, suggesting that pericyte-like cells are primed to sense epithelial injury (permeability changes). Following LPS-induced lung inflammation, increased numbers of pericyte-like cells expressed IL-6, chemokine (C-X-C motif) ligand-1, chemokine (C-C motif) ligand 2/ monocyte chemotactic protein-1, and ICAM-1 in vivo. Sterile lung injury in pericyte-ablated mice was associated with decreased inflammation compared with normal mice. In summary, we found that pericyte-like cells are immune responsive and express diverse chemokines in response to lung injury in vitro and in vivo. Furthermore, pericyte-like cell ablation attenuated inflammation in sterile lung injury, suggesting that these cells play an important functional role in mediating lung inflammatory responses. We propose a model in which pericyte-like cells function as interstitial immune sentinels, detecting proinflammatory molecules released following epithelial barrier damage and participating in recruitment of circulating leukocytes.

Glycosylation is a global target for androgen control in prostate cancer cells.

Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer. We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly upregulated in prostate cancer tissue. These 8 enzymes are under direct control of the androgen receptor (AR) and are linked to the synthesis of important cancer-associated glycans such as sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulfate. Glycosylation has a key role in many important biological processes in cancer including cell adhesion, migration, interactions with the cell matrix, immune surveillance, cell signalling and cellular metabolism. Our results suggest that alterations in patterns of glycosylation via androgen control might modify some or all of these processes in prostate cancer. The prostate is an abundant secretor of glycoproteins of all types, and alterations in glycans are, therefore, attractive as potential biomarkers and therapeutic targets. Emerging data on these often overlooked glycan modifications have the potential to improve risk stratification and therapeutic strategies in patients with prostate cancer.

Immune Response to Exercise During Growth.

Two papers were selected for this commentary. The first paper (Citation 1) suggests that a 10-week, moderate-intensity exercise program performed early after allogeneic hematopoietic stem cell transplantation is feasible in this fragile population, and might improve cell cytotoxicity by redistributing subpopulations of NK cells. This study adds to the growing evidence that enhancing immune cell surveillance (e.g., NK cells) in response to exercise could benefit cancer patients. The second paper (Citation 2) studied neutrophil-related mediators of oxidative stress and inflammatory cytokines in response to exercise in children compared with adults. The authors found age/maturation-related differences in these responses. The paper provides a valuable introduction to the current knowledge of maturational changes in immune mediators' response to exercise. Data about leukocyte function in response to exercise in healthy children and in children with clinical conditions is scant. The need for prospective large scale pediatric clinical exercise studies is clear. Molecular approaches to understand the mechanisms through which physical activity can improve health will help to shape guidelines that optimize the mode, frequency, intensity, and duration of the training intervention.

Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance

Memory CD8+ T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8+ T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8+ T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8+ T cells from pdk1K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)loCD43lo effector-like memory cells. Consequently, antitumor immunity by CD8+ T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8+ T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8+ T-cell responses.

AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE‐mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state‐of‐the‐art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE‐mediated tumour antigen cross‐presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

What can target kidney fibrosis?

Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGFβ inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.