A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis.

Sepsis is a heterogeneous syndrome clinically and biologically, but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4+ neutrophils on sepsis presentation would be associated with mortality. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the emergency department (ED) with suspected sepsis [identified by 2 or greater systemic inflammatory response syndrome (SIRS) criteria and antibiotic receipt] from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were 1) percentage of OLFM4+ neutrophils and 2) OLFM4+ neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4+ neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4+ (≥37.6%), 56% died, compared with 18% with OLFM4+ <37.6% (P = 0.001). The association between OLFM4+ and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) (P < 0.03). In summary, OLFM4+ neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.

Oestrogen receptor-mediated expression of Olfactomedin 4 regulates the progression of endometrial adenocarcinoma.

Endometrial adenocarcinoma is the most common tumour of the female genital tract in developed countries, and oestrogen receptor (ER) signalling plays a pivotal role in its pathogenesis. When we used bioinformatics tools to search for the genes contributing to gynecological cancers, the expression of Olfactomedin 4 (OLFM4) was found by digital differential display to be associated with differentiation of endometrial adenocarcinoma. Aberrant expression of OLFM4 has been primarily reported in tumours of the digestive system. The mechanism of OLFM4 in tumuorigenesis is elusive. We investigated OLFM4 expression in endometrium, analysed the association of OLFM4 with ER signalling in endometrial adenocarcinoma, and examined the roles of OLFM4 in endometrial adenocarcinoma. Expression of OLFM4 was increased during endometrial carcinogenesis, linked to the differentiation of endometrioid adenocarcinoma, and positively related to the expression of oestrogen receptor-α (ERα) and progesterone receptor. Moreover, ERα-mediated signalling regulated expression of OLFM4, and knockdown of OLFM4 enhanced proliferation, migration and invasion of endometrial carcinoma cells. Down-regulation of OLFM4 was associated with decreased cumulative survival rate of patients with endometrioid adenocarcinoma. Our data suggested that impairment of ERα signal-mediated OLFM4 expression promoted the malignant progression of endometrioid adenocarcinoma, which may have significance for the therapy of this carcinoma.

Dendritic cells pulsed with penetratin-OLFM4 inhibit the growth and metastasis of melanoma in mice.

Cancer stem cells (CSCs) can self-renew and differentiate, contributing to tumor heterogeneity, metastasis, and recurrence. Their resistance to therapies, including immunotherapy, underscores the importance of targeting them for complete remission and relapse prevention. Olfactomedin 4 (OLFM4), a marker associated with various cancers such as colorectal cancer, is expressed on CSCs promoting immune evasion and tumorigenesis. However, its potential as a target for CSC-specific immunotherapy remains underexplored. The primary aim of this study is to evaluate the effectiveness of targeting OLFM4 with dendritic cell (DC)-based vaccines in inhibiting tumor growth and metastasis. To improve antigen delivery and immune response, OLFM4 was conjugated with a protein-transduction domain (PTD) from the antennapedia of Drosophila called penetratin, creating a fusion protein (P-OLFM4). The efficacy of DCs pulsed with P-OLFM4 (DCs [P-OLFM4]) was compared to DCs pulsed with OLFM4 (DCs [OLFM4]) and PBS (DCs [PBS]). DCs [P-OLFM4] inhibited tumor growth by 91.2 % and significantly reduced lung metastasis of OLFM4+ melanoma cells by 97 %, compared to the DCs [PBS]. DCs [OLFM4] also demonstrated a reduction in lung metastasis by 59.7 % compared to DCs [PBS]. Immunization with DCs [P-OLFM4] enhanced OLFM4-specific T-cell proliferation, interferon-γ production, and cytotoxic T cell activity in mice. The results indicate that OLFM4 is a viable target for CSC-focused immunotherapy. DC [P-OLFM4] vaccines can elicit robust immune responses, significantly inhibiting tumor growth and metastasis. This strategy holds promise for developing more effective cancer treatments that specifically target CSCs, potentially leading to better patient outcomes by reducing the likelihood of tumor relapse and metastasis.

Serum levels of olfactomedin 4: a biomarker for asthma control state in asthmatics.

BACKGROUND: Neutrophils are a key component of inflammation in asthma. Olfactomedin 4 (OLFM4) is produced by neutrophils and has been reported to be associated with asthma inflammation. We hypothesized that serum OLFM4 may be increased in asthmatic individuals and can assist with predicting asthma control state. METHODS: A total of 79 individuals were enrolled from Shenzhen People's Hospital, China and divided into 3 groups: uncontrolled asthmatics (n=35), controlled asthmatics (n=14), and healthy controls (n=30). The serum OLFM4 level was measured by enzyme-linked immunosorbent assay (ELISA). Clinical characteristics (such as age, gender, allergy history, body mass index (BIM), and smoking history), clinical indicators (such as whole blood count, sputum neutrophil, sputum eosinophil, forced expiratory volume in one second as percentage of predicted volume (FEV1% pred), IgE level, high sensitivity C-reactive protein (hs-CRP), and fractional expiratory nitric oxide (FeNO) were measured and the three groups were compared. The correlation between OLFM4 and the clinical characteristics and indicators was then evaluated. Finally, stepwise multiple regression analysis was performed to determine the contribution of clinical characteristics and clinical indicators influencing serum OLFM4 level. RESULTS: Our results showed that the serum OLFM4 level was increased two-fold in the controlled asthma group (3,450.38±3,000.35 pg/mL) and three-fold in the uncontrolled asthma group (5,084.57±3,425.76 pg/mL), compared to the healthy control group (1,830.11±1,239.70 ng/mL) (P<0.001). We found a positive correlation between serum OLFM4 level and sputum neutrophils (P<0.001). OLFM4 was also found to be related to both hs-CRP level (P=0.007*) and blood neutrophil count (P<0.001). There were no significant associations identified between OLFM4 and age, gender, BMI, allergy, blood eosinophils, blood neutrophils, IgE, FeNO, or FEV1% pred. CONCLUSIONS: Serum OLFM4 levels were increased in patients with asthma (the controlled asthma and uncontrolled asthma groups). There was a significant correlation between serum OLFM4 and levels of sputum neutrophil and hs-CRP, and OLFM4 was also related to both Hs-CRP level and blood neutrophil count. Serum OLFM4 level may serve as a useful biomarker for assessing asthma control state in asthmatic adults.