Higher Levels Of IL-10 Research Articles

Biomarkers of neuropsychiatric dysfunction in intensive care unit survivors: a prospective cohort study.

To assess factors associated with long-term neuropsychiatric outcomes, including biomarkers measured after discharge from the intensive care unit. A prospective cohort study was performed with 65 intensive care unit survivors. The cognitive evaluation was performed through the Mini-Mental State Examination, the symptoms of anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale, and posttraumatic stress disorder was evaluated using the Impact of Event Scale-6. Plasma levels of amyloid-beta (1-42) [Aβ (1-42)], Aβ (1-40), interleukin (IL)-10, IL-6, IL-33, IL-4, IL-5, tumor necrosis factor alpha, C-reactive protein, and brain-derived neurotrophic factor were measured at intensive care unit discharge. Of the variables associated with intensive care, only delirium was independently related to the occurrence of long-term cognitive impairment. In addition, higher levels of IL-10 and IL-6 were associated with cognitive dysfunction. Only IL-6 was independently associated with depression. Mechanical ventilation, IL-33 levels, and C-reactive protein levels were independently associated with anxiety. No variables were independently associated with posttraumatic stress disorder. Cognitive dysfunction, as well as symptoms of depression, anxiety, and posttraumatic stress disorder, are present in patients who survive a critical illness, and some of these outcomes are associated with the levels of inflammatory biomarkers measured at discharge from the intensive care unit.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1β (MIP-1β), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Relationships of Low Serum Levels of Interleukin-10 With Poststroke Anxiety and Cognitive Impairment in Patients With Clinical Acute Stroke.

The relationships among interleukin (IL)-10 levels, anxiety, and cognitive status after stroke remain controversial. We aimed to determine the associations of serum IL-10 levels with poststroke anxiety (PSA) and poststroke cognitive impairment (PSCI). We recruited 350 patients with stroke, of whom only 151 completed a 1-month follow-up assessment. The Mini Mental State Examination (MMSE) and Hamilton Anxiety Scale (HAMA) were used to assess the cognitive status and anxiety, respectively. Serum IL-10 levels were measured within 24 hours of admission. IL-10 levels were significantly lower in the PSA group than in the non-PSA group, and they were negatively associated with HAMA scores (r=-0.371, p<0.001). After adjusting for all potential confounders, IL-10 levels remained an independent predictor of PSA (odds ratio=0.471, 95% confidence interval=0.237-0.936, p=0.032). IL-10 levels were strongly correlated with behavior during interviews, psychic anxiety, and somatic anxiety. Patients without PSCI had higher IL-10 levels were higher in non-PSCI patients than in PSCI patients, and they were positively associated with MMSE scores in the bivariate correlation analysis (r=0.169, p=0.038), and also with memory capacity, naming ability, and copying capacity. However, IL-10 did not predict PSCI in the univariable or multivariable logistic regression. Low IL-10 levels were associated with increased risks of PSA and PSCI at a 1-month follow-up after stroke. Serum IL-10 levels may therefore be helpful in predicting PSA.

The human placenta shapes the phenotype of decidual macrophages

During human pregnancy, placenta-derived extravillous trophoblasts (EVTs) invade the decidua and communicate with maternal immune cells. The decidua distinguishes into basalis (decB) and parietalis (decP). The latter remains unaffected by EVT invasion. By defining a specific gating strategy, we report the accumulation of macrophages in decB. We describe a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome compared with decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ, and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate Tcells. Strikingly, EVT-conditioned media convert decPAMs into a decBAM phenotype. These findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of decB-associated macrophage polarization.

The Role of Nanomaterials and Macrophage Polarization in Inflammation and Cancer Treatment

Macrophages (MΦs) are functionally plastic and can rapidly adopt different phenotypes based on the stimuli they received from their surroundings. For instance, (MΦs) can differentiate into pro-inflammatory M1-type secreting various pro-inflammatory cytokines, e.g., IL-6, IL-12 and TNF-α. This is an essential defensive mechanism against invading pathogens, but also contributes to tissue destruction. On the other hand, M2-type MΦs have immunosuppressive activity, produces high level of anti-inflammatory cytokine IL-10 and mediates tissue repair. Their unique plasticity and the balance in between different phenotypes maintain the immune homeostasis in the lung under healthy conditions. The role of these two forms of MΦs are also evident in cancer biology. While tissue resident MΦs those who are of M1 type are exerting the immune challenge to the tumor cells, the M2 type from the tumor microenvironment (TME) are supporting the growth and progression of cancer cells. Nanodevices are thought to be an ideal agent targeting macrophages owing to their intrinsic nanoscale property suitable for phagocytosis. The induction of MΦs polarization has been employed in various studies, where administration of IL-4 could reprogram the endogenous inflammatory macrophages (M1-type) to anti-inflammatory ones (M2-type), and accelerate resolution of inflammation and lung repair in a STAT6-dependent manner in both LPS and Pseudomonas aeruginosa bacterial pathogen-induced ALI (Acute Lung Injury) mouse models.

Characterization of Regulatory T Cells in Patients Infected by Leishmania Infantum.

High IL-10 levels are pivotal to parasite survival in visceral leishmaniasis (VL). Antigenic stimuli induce IL-10 expression and release of adenosine by CD39/CD73. Due their intrinsic ability to express IL-10 and produce adenosine from extracellular ATP, we evaluated the IL-10, CD39, and CD73 expression by Regulatory T cells (Treg) correlated with VL pathology. Using flow cytometry, Treg cells was analyzed in peripheral blood samples from VL patients (in the presence and absence of Leishmania infantum soluble antigen (SLA)) and healthy individuals (negative endemic control-NEC group), without any treatment. Additionally, IL-10 levels in leukocytes culture supernatant were measured in all groups by ELISA assay. VL patients presented more Treg frequency than NEC group, independently of stimulation. ELISA results demonstrated that SLA induced higher IL-10 expression in the VL group. However, the NEC group had a higher Treg IL-10+ compared to the VL group without stimulation and SLA restored the IL-10 in Treg. Additionally, an increase in Treg CD73+ in the VL group independently of stimuli compared to that in the NEC group was observed. We suggest that Treg are not the main source of IL-10, while the CD73 pathway may be an attempt to modulate the exacerbation of immune response in VL disease.

Clinical utility of cytokine analysis in the diagnosis and efficacy monitoring of vitreoretinal lymphoma.

To investigate the value of cytokine analysis in aqueous humor (AH) for discriminating vitreoretinal lymphoma (VRL) from uveitis and for evaluating the efficacy of intravitreal methotrexate (MTX) injections. This retrospective study was done on 28 VRL patients between 2013 and 2019. AH interleukin (IL)-10, IL-6, IL-8, vascular endothelial growth factor (VEGF), and vascular cell adhesion molecules (VCAM) were measured in 28 VRL patients and 38 uveitis patients. As to the respective examinations for distinguishing VRL from uveitis, the diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. The response to treatment was monitored by observing changes in best-corrected visual acuity (BCVA), ocular manifestation, and AH cytokine levels in 21 patients with VRL who had undergo multiple intravitreal injections of MTX. Compared with uveitis patients, VRL patients had higher IL-10 level (P<0.001) and IL-10/IL-6 ratio (P<0.001), whereas patients with uveitis had significantly higher IL-6 level than those with VRL (P=0.003). An ROC analysis was used to identify the diagnostic threshold values for VRL, and it was found that optimal sensitivity and specificity improved to 94.1% and 100%, respectively, for IL-10/IL-6>1.55 and 88.2% and 81.1%, respectively, for IL-10>76.7 pg/mL. In 21 patients who had undergo repeated injections, improvements in BCVA, clinical remission of VRL and continuous decrease in cytokine levels over time were observed. In those patients, the BCVA correlated with the aqueous levels of IL-10 and IL-6 during the course of disease treatment. The combination of the aqueous cytokine profiles can be instrumental for conventional diagnostic methods and for progression monitoring and treatment response.

Deleting interleukin-10 from myeloid cells exacerbates atherosclerosis in Apoe-/- mice.

Atherosclerosis is initiated by subendothelial retention of lipoproteins and cholesterol, which triggers a non-resolving inflammatory process that over time leads to plaque progression in the artery wall. Myeloid cells and in particular macrophages are the primary drivers of the inflammatory response and plaque formation. Several immune cells including macrophages, T cells and B cells secrete the anti-inflammatory cytokine IL-10, known to be essential for the atherosclerosis protection. The cellular source of IL-10 in natural atherosclerosis progression is unknown. This study aimed to determine the main IL10-producing cell type in atherosclerosis. To do so, we crossed VertX mice, in which IRES-green fluorescent protein (eGFP) was placed downstream of exon 5 of the Il10 gene, with atherosclerosis-prone Apoe-/- mice. We found that myeloid cells express high levels of IL-10 in VertX Apoe-/- mice in both chow and western-diet fed mice. By single cell RNA sequencing and flow cytometry analysis, we identified resident and inflammatory macrophages in atherosclerotic plaques as the main IL-10 producers. To address whether IL-10 secreted by myeloid cells is essential for the protection, we utilized LyzMCre+Il10fl/fl mice crossed into the Apoe-/- background and confirmed that macrophages were unable to secrete IL-10. Chow and western diet-fed LyzMCre+Il10fl/fl Apoe-/- mice developed significantly larger atherosclerotic plaques as measured by en face morphometry than LyzMCre-Il10 fl/flApoe-/-. Flow cytometry and cytokine measurements suggest that the depletion of IL-10 in myeloid cells increases Th17 cells with elevated CCL2, and TNFα in blood plasma. We conclude that macrophage-derived IL-10 is critical for limiting atherosclerosis in mice.

Expression and Prognostic Value of PIK3CA, VEGF, IL-8, IL-10, and RIP2 in Diffuse Large B-Cell Lymphoma.

To explore clinical features and prognostic value of vascular endothelial growth factor (VEGF), interleukin (IL) 8, IL-10, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and receptor-interacting protein-2 (RIP2) in diffuse large B-cell lymphoma (DLBCL). A total of 68 DLBCL patients admitted to the Affiliated Hospital of Hebei Engineering University from January 2017 to June 2021 were included in this retrospective analysis. Serum VEGF was detected by enzyme-linked immunosorbent assay, serum IL-8 and IL-10 were detected by chemiluminescent enzyme immunoassay, and expression of PIK3CA and RIP2 in tumors was detected by immunohistochemistry. The correlation between clinical features of DLBCL and tumor-related index were analyzed. Cox regression was conducted to explore risk factors and hazard ratio. The serum level or expressions of VEGF, IL-8, IL-10, and RIP2 were significantly elevated with the increase of Ann Arbor Stage, International Prognostic Index (IPI) scores, Eastern Cooperative Oncology Group (ECOG) scores, serum lactate dehydrogenase (LDH) level, and the number of extranodal sites (all P < 0.05). Beside, these serum indexes were significantly higher in patients with the presence of extranodal involvement and germinal center B-cell (GCB), but significantly lower in patients with the presence of bone marrow involvement (all P < 0.05). Cox regression analysis for overall survival revealed that high expression of VEGF, high level of serum IL-8, serum IL-10, and RIP2, Ann Arbor Stage (III-IV), number of extranodal sites (>1), serum LDH level (≥245 U/L), IPI scores (3-5), ECOG scores (≥2), and bone marrow involvement were independent risk factors for the prognosis of DLBCL patients (all P < 0.05). The serum levels of VEGF, IL-8, and IL-10, as well as the expression of RIP2 and PIK3CA in tumor tissues, were highly correlated to clinical features of DLBCL, and high expression level of these indexes may have adverse effects for the prognosis of DLBCL patients.

Altered PTPN22 and IL10 mRNA Expression Is Associated with Disease Activity and Renal Involvement in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with very heterogeneous clinical behavior between affected individuals. Therefore, the search for biomarkers clinically useful for the diagnosis, prognosis, and monitoring of the disease is necessary. Here, we determined the association between PTPN22, IL10, OAS2, and CD70 mRNA expression with the clinical characteristics and with the serum levels of IL-10, IFN-γ, and IL-17 in SLE patients. Forty patients with SLE and 34 control subjects (CS) were included, mRNA expression was determined by real-time qPCR and cytokine levels were quantified by a multiplex bead-based immunoassay. Compared to CS, SLE patients showed increased IL10 mRNA and high IL-10 and IL-17 serum levels; in contrast, PTPN22 mRNA and IFN-γ were decreased. PTPN22 and IL10 gene expression was negatively correlated with Mex-SLEDAI score and were notably downregulated in SLE patients with lupus nephritis. Interestingly, SLE patients with renal damage were the ones with the lowest levels of PTPN22 and IL10 mRNA and the highest SLEDAI scores. No associations were observed for OAS2 and CD70 mRNA and IL-10, IL-17, and IFN-γ. In conclusion, we suggest that the assessment of IL10 and PTPN22 mRNA could be useful for monitoring disease activity in SLE patients showing renal involvement.

RBIO-07. HIGHER CSF IL-10 CORRELATE WITH BRAIN ATROPHY AFTER WHOLE BRAIN RADIATION THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract Whole brain radiation therapy (WBRT) to primary central nervous system lymphoma (PCNSL) correlate with brain atrophy and leukoencephalopathy on serial computed tomography or MRI scans, negatively impacting cognitive function and quality of life. We retrospectively evaluated 53 patients with histologically proven PCNSL who underwent cerebrospinal fluid (CSF) examination including β2-MG, sIL2R, CXCL13, and IL-10 preoperatively. All patients were newly diagnosed and followed up every 3 months from the day they were discharged from the hospital. Follow up period is at least 1 year from last day of chemotherapy. Clinical data included patient demographics, radiological and characteristics; whole brain volume (mm2) calculated from BainLabTM automatically, Global Cortical Atrophy (GCA) for global brain atrophy, Medial Temporal Atrophy (MTA) for temporal atrophy, and Fazekas scale for white matter lesions. The unpaired t test and multivariable liner regression were used to examine the clinical, CSF and radiological characteristics of patients. The mean age at symptom onset was 65.2 years (47-85 years). Thirty three of 53 (62%) patients underwent WBRT with chemotherapy (WBRT group). In all patients, multivariable analysis revealed WBRT correlate with brain volume reduction (p=0.0005) and progression of temporal lobe atrophy (p=0.0056). In addition, Age correlated with increasing white matter lesions at 1 year after chemotherapy (p=0.0422). In WBRT group, multivariable analysis indicated that high CSF IL-10 level accelerated brain volume reduction (p=0.0122) and temporal lobe atrophy (p=0.0343) at 6 months after chemotherapy. However, there were no significant factor for influencing brain atrophy at 1 year. Higher IL-10 ( &amp;gt; 100mg/ml) level demonstrated higher brain atrophy rate (p=0.0366) and severe temporal atrophy at 1 year (p=0.0214). In elderly patients with high preoperative CSF IL-10 levels, cerebral atrophy and toxic leukoencephalopathy may progress in short period of time after WBRT. We should consider treatment strategy that avoid WBRT, such as R-MPV chemotherapy, for PCNSL patients.

Plasma exchange and COVID 19

Plasma exchange and COVID 19

High levels of serum IL-10 indicate disease progression, extramedullary involvement, and poor prognosis in multiple myeloma.

Multiple myeloma (MM) is a common malignant hematological tumor in adults, which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins (M protein), leading to bone destruction, hypercalcemia, anemia, and renal insufficiency (Alexandrakis et al., 2015; Yang et al., 2018). Since a large number of new drugs, represented by proteasome inhibitors and immunomodulators, have been successfully used to treat MM, treatment efficacy and survival of patients have been significantly improved. However, due to the high heterogeneity of this disease, patients have responded differently to treatments with these new drugs (Palumbo and Anderson, 2011; Wang et al., 2016; Huang et al., 2020). Growth and survival of MM cells depend on the bone marrow microenvironment, especially numerous inflammatory cytokines secreted by myeloma cells and bone marrow stromal cells, such as vascular endothelial growth factor (VEGF), interleukin (IL)‍-6, transforming growth factor-‍β (TGF‍‍-‍‍β), and IL-10. These cytokines can promote the growth of myeloma cells, induce angiogenesis, and inhibit antitumor immunity, and are often linked to patient prognosis (Kumar et al., 2017). In this era of new drugs, the prognostic values of the serum levels of these cytokines in MM need further evaluation.

Mycobacterium tuberculosis exploits MPT64 to generate myeloid-derived suppressor cells to evade the immune system.

Mycobacterium tuberculosis (Mtb) is a smart and successful pathogen since it can persist in the intimidating environment of the host by taming and tuning the immune system. Mtb releases MPT64 (Rv1980c) protein in high amounts in patients with active tuberculosis (TB). Consequently, we were curious to decipher the role of MPT64 on the differentiating dendritic cells (DCs) and its relation to evading the immune system. We observed that pre-exposure of differentiating DCs to MPT64 (DCMPT64) transformed them into a phenotype of myeloid-derived suppressor cells (MDSCs). DCMPT64 expressed a high level of immunosuppressive molecules PD-L1, TIM-3, nitric oxide (NO), arginase 1, IDO-1, IL-10 and TGF-β, but inhibited the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-12. DCMPT64 chemotaxis function was diminished due to the reduced expression of CCR7. DCMPT64 promoted the generation of regulatory T cells (Tregs) but inhibited the differentiation of Th1 cells and Th17 cells. Further, high lipid and methylglyoxal content, and reduced glucose consumption by DCMPT64, rendered them metabolically quiescent and consequently, reduced DCMPT64 ability to phagocytose Mtb and provided a safer shelter for the intracellular survival of the mycobacterium. The mechanism identified in impairing the function of DCMPT64 was through the increased production and accumulation of methylglyoxal. Hence, for the first time, we demonstrate the novel role of MPT64 in promoting the generation of MDSCs to favor Mtb survival and escape its destruction by the immune system.

Combination of Methotrexate and Leflunomide Is Efficient and Safe for 60 Patients with Rheumatoid Arthritis.

The present work is aimed at exploring the clinical efficacy and safety of methotrexate (MTX) and leflunomide (LEF) combination therapy for rheumatoid arthritis. From June 2019 to June 2021, a total of 120 individuals with rheumatoid arthritis received a diagnosis. Sixty patients each were randomly assigned to the control and observation groups. The observation group received MTX and LEF combo medication while the control group only received MTX treatment. Clinical efficacy, complication incidence, and the alleviation of inflammatory markers, joint pain, and clinical symptoms were compared between the 2 groups. Posttreatment, the observation group had overall response rate of 96.66%, while the control group had 86.67%, with significant differences. Compared with pretreatment, both control and observation group patients showed decreasing trends of IL-1 levels and increasing trends of IL-10 levels posttreatment, with significant differences (P < 0.05). Compared with the control group, patients in the observation group had lower IL-1 and TNF-α levels with significant differences (P < 0.05) and higher levels of IL-10 with significant difference (P < 0.05). In both groups, the pain score and the number of painful joints were much lower than they were prior to treatment. Following treatment, the observation group displayed significantly lower levels of erythrocyte sedimentation rate, rheumatoid factor, and C-reactive protein than the control group (P < 0.05). Clinical measures in the observation group were all lower than those in the control group with statistically significant differences (P < 0.05). Moreover, the incidence rate of adverse reactions showed no significant difference between these 2 groups (P > 0.05). In conclusion, the combination therapy of MTX and LEF is efficacious for rheumatic arthritis.

Emerging Role of Immunomonitoring to Predict the Clinical Outcome of Patients With Malignant Pleural Mesothelioma Treated With Radical Radiation Therapy

The present study aimed at evaluating the baseline immune profile and the immunomodulating effects of radical hemithoracic radiation therapy (RT) in patients affected by malignant pleural mesothelioma (MPM) to identify potential predictive biomarkers of therapy response, toxicity development, and eligibility for further immunotherapeutic treatments. Blood samples were collected from 55 patients with MPM, enrolled in a phase 3 trial comparing radical hemithoracic RT (interventional arm, n=28) with local palliative RT (control arm, n=27). Immunomonitoring was performed before RT, at the end of treatment, and 1 month after therapy, characterizing natural killer cells, B and T lymphocytes, activated CD4 and CD8 T cells, interferon-γ- and tumor necrosis factor-α-producing T helper (Th) 1 cells, regulatory T cells, and Th17 and Th22 lymphocytes, through flow cytometry. Serum levels of interleukin (IL)-6, -8, -10 and mesothelin were quantified through Enzyme-Linked Immunosorbent Assay (ELISA) assays at the same time points. Variations in the immune parameters were investigated by Friedman test and Wilcoxon signed rank post hoc test with Bonferroni correction for multiple testing, while the prognostic effect of immune biomarkers was evaluated through Kaplan-Meier method and Spearman's correlation analysis. Major immune variations were noticed after radical RT compared with palliative treatment, in particular an improvement in activated T cells and in interferon-γ-producing Th1 cells after RT. In the interventional arm, baseline high levels of Th22 and IL-10 and an increase in T cells were associated with an improved survival, whereas a fold increase in serum mesothelin correlated with the development of severe toxicity. An improvement of immunosuppressive regulatory T cells was observed in both arms of treatment. The immunomonitoring performed in patients with MPM revealed potential prognostic biomarkers for radical hemithoracic RT treatment and identified specific immune signatures induced by RT immunomodulation, which could suggest a synergistic effect with an immunotherapeutic treatment.

LOW CD8+ COUNT CORRELATION WITH INFLAMMATORY MARKERS IN ACUTE COVID-19

LOW CD8+ COUNT CORRELATION WITH INFLAMMATORY MARKERS IN ACUTE COVID-19

INPP5A/HLA-G1/IL-10/MMP-21 Axis in Progression of Esophageal Squamous Cell Carcinoma

INPP5A is involved in different cellular events, including cell proliferation. Since INPP5A, HLAG1, IL-10, and MMP-21 genes play fundamental roles in ESCC tumorigenesis, we aimed in this study to clarify the possible interplay of these genes and explore the potential of these chemistries as a predictor marker for diagnosis in ESCC disease. Gene expression analysis of INPP5A, HLAG-1, IL-10, and MMP-21 was performed using relative comparative real-time PCR in 56 ESCCs compared to their margin normal tissues. Immunohistochemical staining was accomplished for INPP5A in ESCCs. Analysis of ROC curves and the AUC were applied to evaluate the diagnostic capability of the candidate genes. High levels of HLA-G1, MMP-21, and IL-10 were detected in nearly 23.2%, 62.5%, and 53.5% of ESCCs compared to the normal tissues, respectively, whereas INPP5A underexpression was detected in 19.6% of ESCCs, which all tested genes indicated significant correlations with each other. The protein expression levels of INPP5A in ESCC tissues were significantly lower than those of the non-tumor esophageal tissues (p = 0.001). Interestingly, the concomitant expression of the INPP5A/HLA-G1, INPP5A/MMP-21, INPP5A/IL-10, HLA-G1/MMP-21, HLA-G1/IL-10, and MMP-21/IL-10 was significantly correlated with several clinicopathological variables. INPP5A, HLA-G1, MMP-21, and IL-10 showed to be the most appropriate candidates to discriminate tumor/non-tumor groups due to the total AUCs of all combinations (>60%). Our results represent a new regulatory axis containing INPP5A/HLAG-1/IL-10/MMP-21 markers in ESCC development and may provide novel insight into the mechanism of immune evasion mediated by the INPP5A/HLAG-1/IL-10/MMP-21 regulatory network in the disease.

Epitope-based minigene vaccine targeting fibroblast activation protein α induces specific immune responses and anti-tumor effects in 4 T1 murine breast cancer model

Fibroblast activation protein (FAPα) is a tumor stromal antigen expressed by cancer-associated fibroblasts (CAFs) in more than 90 % of malignant epithelial carcinomas. FAPα-based immunotherapy has been reported and showed that FAPα-specific immune response can remold immune microenvironment and contribute to tumor regression. Many FAPα-based vaccines have been investigated in preclinical trials, which can elicit strong and durable cytolytic T lymphocytes (CTL) with good safety. However, epitope-based FAPα vaccines are rarely reported. To break tolerance against self-antigens, analogue epitopes with modified peptides at the anchor residues are typically used to improve epitope immunogenicity. To investigate the feasibility of a FAPα epitope-based vaccine for cancer immunotherapy in vivo, we conducted a preclinical study to identify a homologous CTL epitope of human and mouse FAPα and obtained its analogue epitope in BALB/c mice, and explored the anti-tumor activity of their minigene vaccines in 4 T1 tumor-bearing mice. By using in silico epitope prediction tools and immunogenicity assays, immunodominant epitope FAP.291 (YYFSWLTWV) and its analogue epitope FAP.291I9 (YYFSWLTWI) were identified. The FAP.291-based epitope minigene vaccine successfully stimulated CTLs targeting CAFs and exhibited anti-tumor activity in a 4 T1 murine breast cancer model. Furthermore, although the analogue epitope FAP.291I9 enhanced FAP.291-specific immune responses, improvement of anti-tumor immunity effects was not observed. Check of immunosuppressive factors revealed that the high levels of IL-10, IL-13, myeloid-derived suppressor cells and iNOS induced by FAP.291I9 increased, which considered the main cause of the failure of the analogue epitope-based vaccine. Thus, we demonstrated for the first time that the FAP.291 minigene vaccine could induce mouse CTLs and also function as a tumor regression antigen, providing the basis for future studies of FAPα epitope-based vaccines. This study may also be valuable for further improvement of the immunogenicity of analogue epitope vaccines.

Indoleamine 2,3-dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival.

IntroductionIndoleamine 2,3‐dioxygenase (IDO) is an immunosuppressive tryptophan‐depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC.MethodsWe evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real‐time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls.ResultsCompared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease‐specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I–II–III) but negatively correlated in patients with the late‐stage cancer (IV). Tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL‐6 and IL‐10 levels at diagnosis died approximately 1 year after first diagnosis.ConclusionMeasuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.