The use of Three-Dimensional Printing in Orthopaedics: a Systematic Review and Meta-analysis.

Objectives: 3D-printing is a rapidly developing technology with applications in orthopaedics including pre-operative planning, intraoperative guides, design of patient specific instruments and prosthetics, and education. Existing literature demonstrates that in the surgical treatment of a wide range of orthopaedic pathology, using 3D printing shows favourable outcomes. Despite this evidence 3D printing is not routinely used in orthopaedic practice. We aim to evaluate the advantages of 3D printing in orthopaedic surgery to demonstrate its widespread applications throughout the field. Methods: We performed a comprehensive systematic review and meta-analysis. AMED, EMBASE, EMCARE, HMIC, PsycINFO, PubMed, BNI, CINAHL and Medline databases were searched using Healthcare Databases Advanced Search (HDAS) platform. The search was conducted to include papers published before 8th November 2020. Clinical trials, journal articles, Randomised Control Trials and Case Series were included across any area of orthopaedic surgery. The primary outcomes measured were operation time, blood loss, fluoroscopy time, bone fusion time and length of hospital stay. Results: A total of 65 studies met the inclusion criteria and were reviewed, and 15 were suitable for the meta-analysis, producing a data set of 609 patients. The use of 3D printing in any of its recognised applications across orthopaedic surgery showed an overall reduction in operative time (SMD = -1.30; 95%CI: -1.73, -0.87), reduction in intraoperative blood loss (SMD = -1.58; 95%CI: -2.16, -1.00) and reduction in intraoperative fluoroscopy time (SMD = -1.86; 95%CI: -2.60, -1.12). There was no significant difference in length of hospital stay or in bone fusion time post-operatively. Conclusion: The use of 3D printing in orthopaedics leads to an improvement in primary outcome measures showing reduced operative time, intraoperative blood loss and number of times fluoroscopy is used. With its wide-reaching applications and as the technology improves, 3D printing could become a valuable addition to an orthopaedic surgeon's toolbox.

Mef2d potentiates type-2 immune responses and allergic lung inflammation.

Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.

Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy.

Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor ß (TGFß) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.

The evolution of poller screws.

Compared to other techniques, poller screws with intramedullary nailing are technically simple, practical, and reproducible for the fixation of metaphyseal fractures. In addition, poller screws do not require special instruments or hardware and are minimally invasive. This review takes a historical perspective to evaluate poller screws holistically. A non-systematic search on PubMed was performed using 'Poller screw' or 'Blocking screw' to find early use of poller blocking screws. Relevant references from these primary studies were then followed up. In 1999, Krettek et al. first coined the term poller screws after the small metal bollards that block and direct traffic. Poller screws were introduced as an adjunct to aid the union of metaphyseal long bone fractures during intramedullary nailing. However, as more evidence was published, the true effectiveness of poller screws was not appreciated, leading to split opinions. Through our research, we have built upon our understanding of poller screws, and we present a novel classification of poller screws over the years while exploring our novel technique and what we believe to be the fourth generation of poller screws. Currently, there is a paucity of research focussing on poller screws. However, studying the original evidence regarding poller screws through the most recent articles has demonstrated a confusion of research in this field. Therefore, we suggest a more organised approach to classify the use of poller screws.

Novel therapeutic strategies targeting myeloid-derived suppressor cell immunosuppressive mechanisms for cancer treatment.

Cancer is the leading cause of death globally superseded only by cardiovascular diseases, and novel strategies to overcome therapeutic resistance against existing cancer treatments are urgently required. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with potent immunosuppressive capacity against well-established anti-tumour effectors such as natural killer cells (NK cells) and T cells thereby promoting cancer initiation and progression. Critically, MDSCs are readily identified in almost all tumour types and human cancer patients, and numerous studies in the past decade have recognised their role in contributing to therapeutic resistance against all four pillars of modern cancer treatment, namely surgery, chemotherapy, radiotherapy and immunotherapy. MDSCs suppress anti-tumour immunity through a plethora of mechanisms including the well-characterised arginase 1 (Arg1), inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS)-mediated pathways, along with several other more recently discovered. MDSCs are largely absent in healthy homeostatic states and predominantly exist in pathological conditions, making them attractive therapeutic targets. However, the lack of specific markers identified for MDSCs to date greatly hindered therapeutic development, and currently there are no clinically approved drugs that specifically target MDSCs. Methods to deplete MDSCs clinically and inhibit their immunosuppressive function will be crucial in advancing cancer treatment and to overcome treatment resistance. This review provides a detailed overview of the current understandings behind the mechanisms of MDSC-mediated suppression of anti-tumour immunity, and discusses potential strategies to target MDSC immunosuppressive mechanisms to overcome therapeutic resistance.

Increased left ventricular remodelling index in paradoxical low-flow severe aortic stenosis with preserved left ventricular ejection fraction compared to normal-flow severe aortic stenosis.

INTRODUCTION: Patients with paradoxical low-flow (LF) severe aortic stenosis (AS) despite preserved left ventricular ejection fraction (LVEF) appear distinct from normal-flow (NF) patients, showing worse prognosis, more concentric hypertrophy and smaller left ventricular (LV) cavities. The left ventricular remodelling index (LVRI) has been demonstrated to reliably discriminate between physiologically adapted athlete's heart and pathological LV remodelling. METHODS: We studied patients with index echocardiographic diagnosis of severe AS (aortic valve area <1 cm2) with preserved LVEF (>50%). The LVRI was determined by the ratio of the LV mass to the end-diastolic volume, as previously reported, and was compared between patients with LF and NF AS. Patients were prospectively followed up for at least 3 years, and clinical outcomes were examined in association with LVRI. RESULTS: Of the 450 patients studied, 112 (24.9%) had LF AS. While there were no significant differences in baseline clinical profile between LF and NF patients, LVRI was significantly higher in the LF group. Patients with high LVRI (>1.56 g/mL) had increased all-cause mortality (log-rank 9.18, P = 0.002) and were more likely to be admitted for cardiac failure (log-rank 7.61, P = 0.006) or undergo aortic valve replacement (log-rank 18.4, P < 0.001). After adjusting for the effect of age, hypertension, aortic valve area and mean pressure gradient on multivariate Cox regression, high LVRI remained independently associated with poor clinical outcomes (hazard ratio 1.64, 95% confidence interval 1.19-2.25, P = 0.002). CONCLUSION: Pathological LV remodelling (increased LVRI) was more common in patients with LF AS, and increased LVRI independently predicts worse clinical outcomes.

Predictors of futile recanalization after endovascular treatment in acute ischemic stroke: a multi-center study.

Background and objectives: Endovascular thrombectomy (EVT) improves long-term outcomes and decreases mortality in ischemic stroke patients. However, a significant proportion of patients do not benefit from EVT recanalization, a phenomenon known as futile recanalization or reperfusion without functional independence (RFI). In this study, we aim to identify the major stroke risk factors and patient characteristics associated with RFI. Methods: This is a retrospective cohort study of 297 consecutive patients with ischemic stroke who received EVT at three academic stroke centers in China from March 2019 to March 2022. Patient age, sex, modified Rankin Scale (mRS), National Institute of Health Stroke Scale (NIHSS), Alberta stroke program early CT score (ASPECTS), time to treatment, risk factors and comorbidities associated with cerebrovascular diseases were collected, and potential associations with futile recanalization were assessed. RFI was successful reperfusion defined as modified thrombolysis in cerebral infarction (mTICI) ≥ 2b without functional independence at 90 days (mRS ≥ 3). Results: Of the 297 initial patients assessed, 231 were included in the final analyses after the application of the inclusion and exclusion criteria. Patients were divided by those who had RFI (n = 124) versus no RFI (n = 107). Older age (OR 1.041, 95% CI 1.004 to 1.073; p = 0.010), chronic kidney disease (OR 4.399, 0.904-21.412; p = 0.067), and higher 24-h NIHSS (OR 1.284, 1.201-1.373; p < 0.001) were independent predictors of RFI. Conversely, an mTICI score of 3 was associated with a reduced likelihood of RFI (OR 0.402, 0.178-0.909; p = 0.029). Conclusion: In conclusion, increased age, higher 24-h NIHSS and lack of an mTICI score of 3 were independently associated with RFI and have potential prognostic values in predicting patients that are less likely to respond to EVT recanalization therapy.

Left ventricular vortex formation time: emerging clinical applications and limitations.

Vortex formation during left ventricular diastolic filling may provide clinically useful insights into cardiac health. In recent years, there has been growing interest in the measurement of vortex formation time (VFT), especially because it is derived noninvasively. There are important applications of VFT in valvular heart disease, athletic physiology, heart failure and hypertrophic cardiomyopathy. The formation of the vortex as fluid propagates into the left ventricle from the left atrium is important for efficient fluid transport. Quantifying VFT may thus help in evaluating and understanding disease and pathophysiological processes.

7-Day National Institutes of Health Stroke Scale as a surrogate marker predicting ischemic stroke patients' outcome following endovascular therapy.

Background: Early neurological deterioration after endovascular thrombectomy (EVT) is associated with poor prognosis. National Institutes of Health Stroke Scale (NIHSS) score measured at 24 h after EVT may be a better outcome predictor than other methods that focus on changes in NIHSS. Nevertheless, clinical fluctuations in ischemic stroke patients during the immediate phase after symptoms onset are well recognized. Therefore, a delayed NIHSS evaluation may improve prognostic accuracy. We evaluate the 7-day NIHSS in predicting long-term patient outcomes after EVT. Methods: This was a multi-center retrospective cohort study of 300 consecutive ischemic stroke patients with large vessel occlusion who underwent EVT at three-stroke centers in China from August 2018 to March 2022. NIHSS was recorded on admission, pre-EVT, 24 h, and 7 days after EVT. Results: A total of 236 eligible patients were subdivided into two groups: 7-day NIHSS ≤6 and NIHSS >6 post-EVT. 88.29% achieved a favorable outcome (modified Rankin Scale 0-2) in the NIHSS ≤6 group compared to 15.20% in the NIHSS >6 group at 90 days, and an improved favorable outcome in the former group was observed after adjusting for potential confounding factors (adjusted odds ratio 39.7, 95% confidence interval, 17.5-89.7, p < 0.001). Conclusion: The 7-day NIHSS score may be a reliable predictor of 90-day stroke patient outcome after EVT.

Predictors of failure of early neurological improvement in early time window following endovascular thrombectomy: a multi-center study.

Background and objective: Endovascular thrombectomy (EVT) has become the gold standard in the treatment of acute stroke patients. However, not all patients respond well to this treatment despite successful attempts. In this study, we aimed to identify variables associated with the failure of improvements following EVT. Methods: We retrospectively analyzed prospectively collected data of 292 ischemic stroke patients with large vessel occlusion who underwent EVT at three academic stroke centers in China from January 2019 to February 2022. All patients were above 18 years old and had symptoms onset ≤6 h. A decrease of more than 4 points on the National Institute of Health Stroke Scale (NIHSS) after 24 h compared with admission or an NIHSS of 0 or 1 after 24 h was defined as early neurological improvement (ENI), whereas a lack of such improvement in the NIHSS was defined as a failure of early neurological improvement (FENI). A favorable outcome was defined as a modified Rankin scale (mRS) score of 0-2 after 90 days. Results: A total of 183 patients were included in the final analyses, 126 of whom had FENI, while 57 had ENI. Favorable outcomes occurred in 80.7% of patients in the ENI group, in contrast to only 22.2% in the FENI group (p < 0.001). Mortality was 7.0% in the ENI group in comparison to 42.1% in the FENI group (p < 0.001). The multiple logistic regression model showed that diabetes mellitus [OR (95% CI), 2.985 (1.070-8.324), p = 0.037], pre-stroke mRS [OR (95% CI), 6.221 (1.421-27.248), p = 0.015], last known well to puncture time [OR (95% CI), 1.010 (1.003-1.016), p = 0.002], modified thrombolysis in cerebral infarction = 3 [OR (95% CI), 0.291 (0.122-0.692), p = 0.005], and number of mechanical thrombectomy passes [OR (95% CI), 1.582 (1.087-2.302), p = 0.017] were the predictors of FENI. Conclusion: Diabetes mellitus history, pre-stroke mRS, longer last known well-to-puncture time, lack of modified thrombolysis in cerebral infarction = 3, and the number of mechanical thrombectomy passes are the predictors of FENI. Future large-scale studies are required to validate these findings.

Supermicrosurgery: past, present and future.

Supermicrosurgery was popularised in 1997 and is defined as a technique of microvascular anastomosis for single nerve fascicles and vessels 0.3-0.8 mm in diameter. It requires the use of powerful microscopes, ultradelicate microsurgical instruments and specialist dyes. The development of supermicrosurgery has vastly improved the ability of microsurgeons to create true perforator flaps with minimal donor site morbidity for reconstructive surgery and improved the precision of additional microsurgical techniques. This review outlines the origins and history of supermicrosurgery, its current applications in reconstructive surgery (including fingertip reconstructions, true perforator flap surgery, nerve flaps and lymphoedema surgery), supermicrosurgery training and future directions for the field.

Association between the extension of smoke-free legislation and incident acute myocardial infarctions in Singapore from 2010 to 2019: an interrupted time-series analysis.

BACKGROUND: We examined the association between smoke-free laws implemented in the outdoors and the common areas of residential apartment blocks and reported acute myocardial infarctions (AMI) in Singapore. METHODS: We used an interrupted time-series design and seasonal autoregressive integrated moving average models to examine the effect of the smoke-free law extensions in 2013 (common areas of residential blocks, covered pedestrian linkways, overhead bridges and within 5 m of bus stops), 2016 (parks) and 2017 (educational institutions, buses and taxis) on the monthly incidence rate of AMIs per 1 000 000 population. RESULTS: We included 133 868 AMI reports from January 2010 to December 2019. Post-2013, there was a decrease in the AMI incidence trend (ß=-0.6 per month, 95%CI -1.0 to -0.29) and 2097 (95% CI 2094 to 2100) more AMIs may have occurred without the extension. There was a significant step-decline in male AMIs and a non-significant step-increase in female AMIs post-2013. Those 65 years and older experienced a greater decline to the postlegislation 2013 trend (ß=-5.9, 95% CI -8.7 to -3.1) compared with those younger (ß=-0.4, 95% CI -0.6 to -0.2), while an estimated 19 591 (15 711 to 23472) additional AMI cases in those 65 years and above may have occurred without the extension. We found a step-increase in monthly AMI incidence post-2016 (ß=14.2, 95%CI 3.3 to 25.0). CONCLUSION: The 2013 smoke-free law extension to residential estates and other outdoor areas were associated with a decline in AMIs and those above the age of 65 years and men appeared to be major beneficiaries. Additional epidemiological evidence is required to support the expanded smoke-free legislation to parks, educational institutions, buses and taxis.

Using Pre-Clinical Studies to Explore the Potential Clinical Uses of Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem cells.

Recent studies of exosomes derived from mesenchymal stem cells (MSCs) have indicated high potential clinical applications in many diseases. However, the limited source of MSCs impedes their clinical research and application. Most recently, induced pluripotent stem cells (iPSCs) have become a promising source of MSCs. Exosome therapy based on iPSC-derived MSCs (iMSCs) is a novel technique with much of its therapeutic potential untapped. Compared to MSCs, iMSCs have proved superior in cell proliferation, immunomodulation, generation of exosomes capable of controlling the microenvironment, and bioactive paracrine factor secretion, while also theoretically eliminating the dependence on immunosuppression drugs. The therapeutic effects of iMSC-derived exosomes are explored in many diseases and are best studied in wound healing, cardiovascular disease, and musculoskeletal pathology. It is pertinent clinicians have a strong understanding of stem cell therapy and the latest advances that will eventually translate into clinical practice. In this review, we discuss the various applications of exosomes derived from iMSCs in clinical medicine.

Prophylactic antibiotic use for infective endocarditis: a systematic review and meta-analysis.

OBJECTIVES: Infective endocarditis (IE) is a devastating disease with a 50% 1-year mortality rate. In recent years, medical authorities across the globe advised stricter criteria for antibiotic prophylaxis in patients with high risk of IE undergoing dental procedures. Whether such recommendations may increase the risk of IE in at-risk patients must be investigated. DESIGN: Prospectively registered systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Scopus and ClinicalTrials.gov were searched through 23 May 2022, together with an updated search on 5 August 2023. ELIGIBILITY CRITERIA: All primary studies reporting IE within 3 months of dental procedures in adults >18 years of age were included, while conference abstracts, reviews, case reports and case series involving fewer than 10 cases were excluded. DATA EXTRACTION AND SYNTHESIS: All studies were assessed by two reviewers independently, and any discrepancies were further resolved through a third researcher. RESULTS: Of the 3771 articles screened, 38 observational studies fit the inclusion criteria and were included in the study for subsequent analysis. Overall, 11% (95% CI 0.08 to 0.16, I2=100%) of IE are associated with recent dental procedures. Streptococcus viridans accounted for 69% (95% CI 0.46 to 0.85) of IE in patients who had undergone recent dental procedures, compared with only 21% (95% CI 0.17 to 0.26) in controls (p=0.003). None of the high-risk patients developed IE across all studies where 100% of the patients were treated with prophylactic antibiotics, and IE patients are 12% more likely to have undergone recent dental manipulation compared with matched controls (95% CI 1.00 to 1.26, p=0.048). CONCLUSIONS: Although there is a lack of randomised control trials due to logistic difficulties in the literature on this topic, antibiotic prophylaxis are likely of benefit in reducing the incidence of IE in high-risk patients after dental procedures. Further well-designed high-quality case-control studies are required. TRIAL REGISTRATION NUMBER: CRD42022326664.

Type 1 and type 2 cytokine-mediated immune orchestration in the tumour microenvironment and their therapeutic potential.

Cancer remains the second leading cause of death worldwide despite modern breakthroughs in medicine, and novel treatments are urgently needed. The revolutionary success of immune checkpoint inhibitors in the past decade serves as proof of concept that the immune system can be effectively harnessed to treat cancer. Cytokines are small signalling proteins with critical roles in orchestrating the immune response and have become an attractive target for immunotherapy. Type 1 immune cytokines, including interferon γ (IFNγ), interleukin-12 (IL-12), and tumour necrosis factor α (TNFα), have been shown to have largely tumour suppressive roles in part through orchestrating anti-tumour immune responses mediated by natural killer (NK) cells, CD8+ T cells and T helper 1 (Th1) cells. Conversely, type 2 immunity involving group 2 innate lymphoid cells (ILC2s) and Th2 cells are involved in tissue regeneration and wound repair and are traditionally thought to have pro-tumoural effects. However, it is found that the classical type 2 immune cytokines IL-4, IL-5, IL-9, and IL-13 may have conflicting roles in cancer. Similarly, type 2 immunity-related cytokines IL-25 and IL-33 with recently characterised roles in cancer may either promote or suppress tumorigenesis in a context-dependent manner. Furthermore, type 1 cytokines IFNγ and TNFα have also been found to have pro-tumoural effects under certain circumstances, further complicating the overall picture. Therefore, the dichotomy of type 1 and type 2 cytokines inhibiting and promoting tumours respectively is not concrete, and attempts of utilising these for cancer immunotherapy must take into account all available evidence. This review provides an overview summarising the current understanding of type 1 and type 2 cytokines in tumour immunity and discusses the prospects of harnessing these for immunotherapy in light of previous and ongoing clinical trials.

A retrospective analysis of the definitive management of open talus fractures at a major trauma centre, comparing ORIF to FUSION: cohort study and audit of BOAST 4 guidelines.

PURPOSE: Open talus fractures are notoriously difficult to manage, and they are commonly associated with a high level of complications including non-union, avascular necrosis and infection. Currently, the management of such injuries is based upon BOAST 4 guidelines although there is no suggested definitive management, and thus, definitive management is based upon surgeon preference. The key principles of open talus fracture management which do not vary between surgeons are early debridement, orthoplastic wound care, anatomic reduction and definitive fixation whenever possible. However, there is much debate over whether the talus should be preserved or removed after open talus fracture/dislocation and proceeded to tibiocalcaneal fusion. METHODS: A review of electronic hospital records for open talus fractures from 2014 to 2021 returned fourteen patients with fifteen open talus fractures. Seven cases were initially managed with ORIF, and five cases were definitively managed with FUSION, while the others were managed with alternative methods. We collected patient's age, gender, surgical complications, surgical risk factors and post-treatment functional ability and pain and compliance with BOAST guidelines. The average follow-up of the cohort was 4 years and one month. EQ-5D-5L and FAAM-ADL/Sports score was used as a patient reported outcome measure. Data were analysed using the software PRISM. RESULTS: Comparison between FUSION and ORIF groups showed no statistically significant difference in EQ-5D-5L score (P = 0.13), FAAM-ADL (P = 0.20), FAAM-Sport (P = 0.34), infection rate (P = 0.55), surgical times (P = 0.91) and time to weight bearing (P = 0.39), despite a higher proportion of polytrauma and Hawkins III and IV fractures in the FUSION group. CONCLUSION: FUSION is typically used as second line to ORIF or failed ORIF. However, there is a lack of studies that directly compared outcome in open talus fracture patients definitively managed with FUSION or ORIF. Our results demonstrate for the first time that FUSION may not be inferior to ORIF in terms of patient functional outcome, infection rate and quality of life, in the management of patients with open talus fracture patients. Of note, as open talus fractures have increased risks of complications such as osteonecrosis and non-union, FUSION should be considered as a viable option to mitigate these potential complications in these patients.

Air Pollution and Ischaemic Stroke.

Air pollution is a significant contributor of cardiovascular diseases, including ischaemic stroke (IS), with substantial mortality and morbidity. However, associations between air pollution and IS remain unclear. Limited data are available on the relationship between IS and individual air pollutants. In this systematic review, we present an overview of the current literature about various individual ambient air pollutants that are believed to contribute towards incidence of hospitalization and mortality related to IS.

Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and is largely refractory to current immunotherapeutic interventions. The lack of efficacy of existing cancer immunotherapies in CRC reflects the complex nature of the unique intestinal immune environment, which serves to maintain barrier integrity against pathogens and harmful environmental stimuli while sustaining host-microbe symbiosis during homeostasis. With their expression by barrier epithelial cells, the cytokines interleukin-25 (IL-25) and IL-33 play key roles in intestinal immune responses, and have been associated with inappropriate allergic reactions, autoimmune diseases and cancer pathology. Studies in the past decade have begun to uncover the important roles of IL-25 and IL-33 in shaping the CRC tumour immune microenvironment, where they may promote or inhibit tumorigenesis depending on the specific CRC subtype. Notably, both IL-25 and IL-33 have been shown to act on group 2 innate lymphoid cells (ILC2s), but can also stimulate an array of other innate and adaptive immune cell types. Though sometimes their functions can overlap they can also produce distinct phenotypes dependent on the differential distribution of their receptor expression. Furthermore, both IL-25 and IL-33 modulate pathways previously known to contribute to CRC tumorigenesis, including angiogenesis, tumour stemness, invasion and metastasis. Here, we review our current understanding of IL-25 and IL-33 in CRC tumorigenesis, with specific focus on dissecting their individual function in the context of distinct subtypes of CRC, and the potential prospects for targeting these pathways in CRC immunotherapy.

An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis.

Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.