Urinary Neopterin Research Articles

Asymmetric Dimethylarginine Concentrations Decrease in Patients with HIV Infection under Antiretroviral Therapy

In HIV-infected patients, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor and cardiovascular risk factor asymmetric dimethylarginine (ADMA) are documented, and levels correlate with markers of immune activation, such as neopterin. In this study, the effect of antiretroviral therapy (ART) on arginine, ADMA and symmetric dimethylarginine (SDMA) levels was investigated and related to changes of immune activation markers and lipids. Concentrations of ADMA, SDMA, arginine, C-reactive protein (CRP) and neopterin were determined in 112 HIV-infected patients after 12 months of successful ART, as reflected by undetectable HIV RNA levels, and compared to baseline levels. ADMA, SDMA, arginine and urine neopterin levels were determined by HPLC, and plasma neopterin concentrations by ELISA. Disease activity before and after treatment was monitored by determination of HIV RNA levels and CD4(+) T-cell counts. Lipids and CRP were determined by routine laboratory assays. Under treatment with ART, concentrations of ADMA, SDMA and arginine dropped in parallel with decreasing HIV RNA levels and neopterin concentrations, while cholesterol, triglyceride levels and CD4(+) T-cell counts increased. CRP levels did not change. After ART, a significant inverse association between ADMA and plasma cholesterol was observed. Successful ART, defined by HIV RNA levels below the limit of detection, leads to decreasing levels of methylated arginines and immune activation markers. Thus, it is unlikely that disturbances of dimethylarginine metabolism account for the increased risk of cardiovascular events of HIV-infected patients under ART.

OC-068 Albumin is central in mediating the cardio-renal dysfunction of cirrhosis: a study in analbuminaemic rats

IntroductionAlbumin is a multifunctional protein which is reduced in concentration and function in liver disease. Albumin infusion prevents and improves renal dysfunction in patients with advanced liver failure but the...

Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance

This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F2t (8-epi-PGF2α) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2α levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.

Prognostic Significance of Serum Retinol, Serum Alpha-Tocopherol, and Urinary Neopterin in Patients with Head and Neck Carcinoma Treated with External Beam Radiation

High serum or urinary neopterin concentrations are associated with poor prognosis in patients with tumors of different primary locations, but reports on neopterin in patients with head and neck carcinoma are relatively less numerous. It has been established that decreased circulating concentrations of retinol and alpha-tocopherol are common in this population. We have evaluated the prognostic significance of urinary neopterin, serum retinol, and alpha-tocopherol in 44 patients with head and neck carcinoma. Urinary neopterin, serum retinol, and alpha-tocopherol were determined with high-performance liquid chromatography. High urinary neopterin and low serum retinol were predictive of poor prognosis, while the prognostic significance of low alpha-tocopherol was of borderline significance. Serum retinol significantly decreased during external beam radiation, but a less marked decrease of alpha-tocopherol during therapy did not reach statistical significance. An increase of urinary neopterin was evident late during the course of treatment. In conclusion, high urinary neopterin and low serum retinol are predictive of poor prognosis in patients with head and neck carcinoma.

577 ALBUMIN IS CENTRAL IN MEDIATING THE CARDIO-RENAL DYSFUNCTION OF CIRRHOSIS: A STUDY IN ANALBUMINAEMIC RATS

Introduction Albumin is a multifunctional protein which is reduced in concentration and function in liver disease. Albumin infusion prevents and improves renal dysfunction in patients with advanced liver failure but the mechanisms of its beneficial properties are unclear. We hypothesised that albumin is central in the maintenance of cardio-renal function in cirrhosis and albumin impairment worsens outcome. In order to answer this question we investigated analbuminaemic rats, characterised by lack of albumin but with normal protein concentration, following induction of cirrhosis with bile duct ligation (BDL). Methods Male Sprague-Dawley (SD) and Nagase analbuminaemic (NAR) rats were studied 6 weeks after BDL or sham surgery (n=6 sham-SD, 8 sham-NAR, 7 SD-BDL, 7 NAR-BDL). Rats underwent systemic mean arterial pressure (MAP) and portal pressure (PP) assessment under terminal anaesthesia. Plasma and urine were collected for measurements of renal function and protein profile. Plasma renin activity (PRA) was measured as a marker of cardio-renal dysfunction. Urinary neopterin, a marker of macrophage activation was assessed. Results NARs showed plasma total protein concentration similar to SD despite lack of albumin before (72±15 vs 82±8) and after BDL (67±7 vs 75±22). After BDL both groups of animals showed histological evidence of severe liver damage, though the NARs showed a significantly worse systemic haemodynamics with lower MAP (p=0.01), evidence of renal dysfunction indicated by higher plasma creatinine and higher PRA (p Conclusion A lack of albumin was associated with a raised PRA and a marked deterioration in systemic haemodynamics and renal function after liver injury (BDL), despite normal total plasma protein concentration. This worsened outcome in the absence of albumin strongly supports the central role of albumin in maintenance of cardio-renal function in liver failure and may indicate that albumin plays a crucial role in moderating inflammation. Competing interests None declared.

Stress system dynamics during "life as it is lived": an integrative single-case study on a healthy woman.

Little is known about the dynamic characteristics of stress system activity during “life as it is lived”. Using as representative a study design as possible, this investigation sought to gain insights into this area. A healthy 25-year-old woman collected her entire urine over a period of 63 days in 12-h intervals (126 measurements) to determine cortisol and neopterin (immune activation marker) levels. In addition, she filled out questionnaires on emotional state and daily routine in 12-h intervals, and was interviewed weekly to identify emotionally negative and positive everyday incidents. Adjusted cross-correlational analyses revealed that stressful incidents were associated with cyclic response patterns in both urinary cortisol and urinary neopterin concentrations. Urinary cortisol levels first decreased 12–24 h after stressful incidents occurred (lag 1: −.178; p = 0.048) and then increased a total of 72–84 h later (lag 6: +.224; p = 0.013). Urinary neopterin levels first increased 0–12 h before the occurrence of stressful incidents (−lag 1: +.185; p = 0.040) and then decreased a total of 48–60 h following such stressors (lag 4: −.181; p = 0.044). Decreases in urinary neopterin levels were also found 24–36 and 48–60 h after increases in pensiveness (lag 2: −.215; p = 0.017) and depressiveness (lag 4: −.221; p = 0.014), respectively. Findings on emotionally positive incidents sharply contrasted with those dealing with negative experiences. Positive incidents were followed first by urinary cortisol concentration increases within 12 h (lag 0: +.290; p = 0.001) and then by decreases after a total of 60–72 h (lag 5: −.186; p = 0.039). Urinary neopterin levels first decreased 12–24 h before positive incidents occurred (−lag 2: −.233; p = 0.010) and then increased a total of 12–24 h following these incidents (lag 1: +.222; p = 0.014). As with previous investigations on patients with systemic lupus erythematosus (SLE), this study showed that stress system response can be considerably longer and more complex and differentiated than findings from conventional group studies have suggested. Further integrative single-case studies will need to be conducted in order to draw firm conclusions about stress system dynamics under real-life conditions.

Evaluation of Serum and Urinary Levels of some Pteridine Pathway Components in Healthy Turkish Children

Abstract Neopterin, as a non-conjugated pteridine, is synthesized from guanosine triphosphate and its production is upregulated upon the activation of cellular immune response. Alterations of pteridines in body fluids are known to correlate well with existing diseases and stages, prognosis, clinical outcomes and survival data. It is of advantage to have a pteridine database of healthy volunteers to determine normal values. Thereby, especially in children there is no detailed study on pteridine levels. The aim of this study is to initiate the establishment of pteridine database of healthy children in our country. Serum neopterin levels were analysed by enzyme-linked immunosorbent assay. Urinary neopterin and biopterin levels and serum kynurenine, tryptophan levels and kynurenine/tryptophan ratio as an estimate of tryptophan breakdown were assessed with high-pressure liquid chromatography in serum and urine samples of 55 children aged between 3 months and 10 years. The results were evaluated within the subgroups of different ages and sex. Pteridine pathway components were found to be higher in children compared to adults. Higher levels of pteridine pathway components observed within the first years of life may reflect the rapid maturation of the immune system, and environmental adaptation and/or insufficiency of defence systems. On the other hand, it may also relate to a higher frequency of infections not (yet) manifested clinically.

Comparison of a commercial urinary neopterin radioimmunoassay with high performance liquid chromatography

Background: The determination of urinary neopterin using high performance liquid chromatography (HPLC) has routinely been performed in Innsbruck since the middle of the 1980s. The aim was to compare the HPLC method with a commercially available radioimmunoassay. Methods: Neopterin to creatinine ratios were calculated in the urine of 33 healthy volunteers (33±7.3 years) collected at eight given time points. Neopterin and creatinine were simultaneously determined by HPLC and by radioimmunoassay (RIA; BRAHMS; neopterin) and an enzymatic method (Roche; creatinine), respectively. Assays were compared with Bland-Altman plots and Passing-Bablok regression analysis. Results: Neopterin to creatinine ratios ranged from 62 to 490 μmol/mol (HPLC) and from 17 to 425 μmol/mol (RIA-enzymatic combined). The ratios were on average 17.3% lower using the combined RIA-enzymatic method compared to the HPLC method. Neopterin concentrations measured by RIA were only slightly lower (on average 4.9%) than by the HPLC and the regression analysis revealed a good accordance with linearity. In contrast, creatinine concentrations by the enzymatic method were on average 12.8% higher than by HPLC. Conclusions: There is a marked bias between HPLC and the combined RIA-enzymatic method for measurement of urinary neopterin to creatinine ratios which has to be considered when methods are switched during the follow-up of patients.

Comparison of a commercial urinary neopterin radioimmunoassay with high performance liquid chromatography

The determination of urinary neopterin using high performance liquid chromatography (HPLC) has routinely been performed in Innsbruck since the middle of the 1980s. The aim was to compare the HPLC method with a commercially available radioimmunoassay. Neopterin to creatinine ratios were calculated in the urine of 33 healthy volunteers (33±7.3 years) collected at eight given time points. Neopterin and creatinine were simultaneously determined by HPLC and by radioimmunoassay (RIA; BRAHMS; neopterin) and an enzymatic method (Roche; creatinine), respectively. Assays were compared with Bland-Altman plots and Passing-Bablok regression analysis. Neopterin to creatinine ratios ranged from 62 to 490 μmol/mol (HPLC) and from 17 to 425 μmol/mol (RIA-enzymatic combined). The ratios were on average 17.3% lower using the combined RIA-enzymatic method compared to the HPLC method. Neopterin concentrations measured by RIA were only slightly lower (on average 4.9%) than by the HPLC and the regression analysis revealed a good accordance with linearity. In contrast, creatinine concentrations by the enzymatic method were on average 12.8% higher than by HPLC. There is a marked bias between HPLC and the combined RIA-enzymatic method for measurement of urinary neopterin to creatinine ratios which has to be considered when methods are switched during the follow-up of patients.

4223 POSTER Urinary Neopterin Concentrations at Screening Predict Serious Adverse Events in Cancer Patients Enrolled in Clinical Trials

4223 POSTER Urinary Neopterin Concentrations at Screening Predict Serious Adverse Events in Cancer Patients Enrolled in Clinical Trials

Elevated Urinary Neopterin Levels Are Associated with Cardiac and Functional Impairment in Patients with Chronic Systolic Heart Failure

Elevated Urinary Neopterin Levels Are Associated with Cardiac and Functional Impairment in Patients with Chronic Systolic Heart Failure

Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience

In every newborn with even mild hyperphenylalaninemia (HPA) tetrahydrobiopterin (BH(4)) deficiencies need to be excluded as soon as possible. Differential diagnosis is most commonly performed by analysis of urinary neopterin and biopterin. In 2005 a new method for the measurement of neopterin, biopterin and other pterins in dried blood spot (DBS) on filter paper was introduced. In order to evaluate the usefulness of this method as a standard tool for differential diagnosis of HPAs we analyzed neopterin, biopterin, pterin and dihydropteridine reductase activity in DBS from 362 patients with HPA over the period of five years. Age-dependent reference values were established for the HPA population. Sixty-four patients with BH(4) deficiency (27 patients with 6-pyruvoyl-tetrahydropterin synthase deficiency, seven with GTP cyclohydrolase I deficiency, and 30 with dihydropteridine reductase) were identified. Reference values for neopterin and biopterin in DBS were calculated for each of the variants. 6-pyruvoyl-tetrahydropterin synthase and GTP cyclohydrolase I deficiency can be diagnosed by neopterin and biopterin analysis alone, while for diagnosis of dihydropteridine reductase deficiency additional determination of enzyme activity from the same DBS is essential. Regarding test sensitivity, the interpretation of neopterin and biopterin concentration per hemoglobin is more valid than the interpretation of neopterin and biopterin per liter. Percentage of biopterin, of the sum of neopterin and biopterin should always be calculated. In addition, determination of hemoglobin concentration is essential as a measure for efficient extraction of neopterin and biopterin. Although the measurement of neopterin and biopterin in urine is more sensitive due to the higher concentrations present, our data prove the usefulness of their measurement from DBS for the routine diagnosis of BH(4) deficiencies.

Urinary Neopterin in Patients with Metastatic Colon Cancer Treated with Patupilone

Abstract Despite increased efficacy of regimens combining cytotoxic drugs and targeted agents, most patients with metastatic colorectal cancer will ultimately die of the disease. Only a limited number of drugs have reproducible activity in therapy of this tumor, and new active agents are urgently needed. Promising results in the therapy of metastatic colorectal cancer have been reported for patupilone, an epothilone analogue. Similarly to taxanes, the cytotoxic mechanism of epothilones involves the stabilization of microtubules. Increased serum or urinary concentrations of neopterin have been described in patients with tumors of different primary locations, including colorectal cancer. Neopterin concentrations were reported to increase during the administration of cytotoxic agents, including taxane-based chemotherapy. We have studied serum neopterin in patients with colorectal cancer before and during the therapy with patupilone. Urinary neopterin/creatinine concentrations were determined with highperformance liquid chromatography. Increased urinary neopterin concentrations were observed at baseline in the majority of the patients. In most patients, neopterin concentrations further increased during the therapy, and a significant increase of urinary neopterin was observed in patients with normal baseline neopterin concentrations. A trend of decreased survival was observed for patients with high initial neopterin concentration. In conclusion, urinary neopterin is increased in colorectal cancer patients presenting for second or higher line of treatment. An increase of urinary neopterin during patupilone therapy suggests an activation of immune response by this agent.

Correlation of Peripheral Blood CD14+CD16+ Monocytes, Urinary Neopterin and the Risk Factors of Atherosclerosis in Patients with Breast Carcinoma

Abstract Monocytes/macrophages are thought to play a fundamental role in the development of vascular lesions in atherosclerosis. In the present study, we evaluated circulating CD14+CD16+ monocytes, laboratory parameters of the risk of atherosclerosis, including serum cholesterol, homocysteine and C-reactive protein, urinary neopterin, serum a-tocopherol and retinol along with carotid intima-media thickness in patients with breast carcinoma. A significant correlation was observed between the absolute numbers of CD14+CD16+ monocytes, serum HDL cholesterol and triglyceride concentrations. In conclusion, present data extend the observation of an association between peripheral blood CD14+CD16+ monocyte counts and lipid metabolism to cancer patients. No correlation of CD14+CD16+ monocyte counts with urinary neopterin concentrations was observed.

Evaluation of Changes in Immune System of Operating Room Personnel by Measurement of Urinary Neopterin Concentrations

Abstract Today it is known that neopterin is mainly produced by activated macrophages and a marker of immune activation and macrophage activity. Increased neopterin concentrations are observed in diseases related to cellular immunity including occupational pathologies. The major goal of the present study was to evaluate the possible alteration of neopterin levels in operating room personnel, and also to show whether screening of neopterin may be useful to monitor the effect of occupational anesthetic exposure on the cellular immune system. Therefore, urinary neopterin to creatinine levels in both, exposed workers (n = 40) and healthy volunteers (n = 30), were measured by using high-performance liquid chromatography. At the same time, the correlation among urinary neopterin levels and working years, age, and smoking status were evaluated. Compared to controls, urinary neopterin levels in the exposed group were increased (controls: 85 ± 16 μmol/mol creatinine, workers: 151 ± 39 μmol/mol creatinine; p <0.05). The findings suggest that the follow up of neopterin levels may have diagnostic value in possible occupational exposure-related immune system disorders. Moreover, its biological monitoring should be performed in workplaces for clinical diagnosis and prognosis.

Effects of Inhalation Anesthetics on the Profile of Urinary Neopterin as an Immune Marker in Patients who Underwent Laparoscopic Cholecystectomy

Abstract It has been claimed that inhalational anesthetics affect many phases of immune response. Although, there are a lot of studies on the effects of widely used anaesthetic agents and methods on the immune system, there are only a few studies to show the effects by evaluation of neopterin concentrations as an important marker of cellular immunity. This study was done to evaluate possible effects of inhalation anesthetics, such as desflurane, isoflurane, and sevoflurane on the immune system by measuring urinary neopterin concentrations in patients who underwent laparoscopic cholecystectomy. The study is randomized, prospective and double blind. Urinary neopterin was measured in patients submitted to general anesthesia with either desflurane (n = 20) or isoflurane (n = 11), or sevoflurane (n = 13) in laparoscopic cholecystectomy. Urine samples were collected preoperatively, at 2nd and 24th hours post-operatively and the neopterin per creatinine concentrations were measured by using high-performance liquid chromatography. The preoperative neopterin levels were similar across the study groups. Variance analysis of repeated measures showed an effect of time (p <0.05): Neopterin concentrations increased over time, but the effect of different anesthetics on neopterin was similar. The mean increases in neopterin concentrations were similar among all the applied anesthetics. In conclusion, this report shows changes of immune response by investigation of neopterin in urine samples during 24 hours in patients exposed to three different inhalational anesthetic agents sevoflurane, desflurane and isoflurane in laparoscopic cholecystectomy.

Macrophage activation is associated with poorer long‐term outcomes in renal transplant patients

Long-term graft and patient survival after renal transplantation are largely determined by progression of chronic allograft dysfunction and cardiovascular disease. Inflammation plays a crucial role in both disease processes. We prospectively analyzed the association of early peri-transplant inflammatory burden on long-term outcomes in 144 consecutive deceased donor renal allograft recipients. Single time point and cumulative levels of markers of acute phase response (serum amyloid A [SAA] and C-reactive protein [SCRP]) and macrophage activation (serum and urine neopterin) were measured daily during the immediate post-operative period. Mean patient follow-up was 16 yr. Graft and patient survival rates at one-, five-, and 10-yr were 90%, 70%, and 51%, and 97%, 77%, and 59%, respectively. Graft loss occurred in 90 patients, of whom 71 died with a functioning graft and 19 returned to dialysis. CRP, SAA and neopterin (NEOP) levels were all elevated post-operatively. High levels of NEOP, in contrast to SAA or SCRP, were associated with poorer graft and patient survival (p < 0.05), specifically with death from cardiovascular events and cytomegalovirus IgG positivity. These findings strongly suggest that early post-transplant macrophage activation, as reflected by NEOP levels, is associated with poorer long-term graft and patient survival.

The Use of Serum, Urine, and Fecal Neopterin to Determine Disease Activity in Crohnʼs Disease

The Use of Serum, Urine, and Fecal Neopterin to Determine Disease Activity in Crohnʼs Disease

The Use of Serum, Urine, and Fecal Neopterin to Determine Disease Activity in Ulcerative Colitis

Purpose: There are few noninvasive biomarkers which correlate with disease activity in ulcerative colitis (UC). The aim of this study was to determine if serum, urine, or fecal neopterin concentrations were associated with disease activity as determined by the Simple Clinical Colitis Activity (SCCAI) and Disease Activity Indices (DAI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum albumin and, fecal lactoferrin. Methods: We prospectively enrolled a total of 52 outpatients with UC (29 clinically in remission, 23 active). Disease was considered active if the SCCAI was ≥3. Fecal (n=50), urine (n=115) and serum (n=120) samples were collected from healthy controls for neopterin measurement. Due to non-normality of data, medians and ranges are present. Mann-Whitney or Kruskal-Wallis tests, and Spearman's correlation coefficients were employed. Results: Fecal neopterin was significantly higher in UC patients compared to controls (95.2 (7, 248) vs. 12.0 (3, 379) ng/g; p<0.001); median serum neopterin levels were higher in controls, although the range was wider in UC patients (4.5 (2.3, 14.6) v 2.9 (1.5, 1.5, 57.3), p<0.001); additionally, fecal neopterin and serum neopterin were higher among those with active disease (active v. inactive fecal neopterin 135 (56, 248) and 63 (7, 182), and serum neopterin 3.8 (1.5, 21.3) v. 2.3 (1.5, 57.3), both p < 0.05). No significant difference in urine neopterin values was detected in controls vs. UC patients (p=0.4138). Urine neopterin was weakly but significantly correlated with Hb (-0.37), Hct (-0.43), albumin (-0.38) but not with SCCAI, DAI, CRP, or ESR. Serum neopterin correlated with SCCAI (0.30), Hct (-0.30), Albumin (-0.43), CRP (0.37), and ESR (0.35) but not with Hb or DAI. Fecal neopterin correlated with SCCAI (0.48), and ESR (0.40) but not with DAI, Hb, Hct, Albumin, or CRP. Conclusion: Fecal neopterin was significantly greater in patients with UC vs. controls, and was significantly higher among those with active disease. For patients in remission, that suggests the likelihood of ongoing subclinical intestinal inflammation. Urine neopterin did not distinguish UC patients (active or remission) from healthy controls. Although differences were seen in distributions of serum neopterin between UC groups and controls, it is unclear if there is a single mechanism to explain this.

Urinary neopterin does not reflect the local antitumor immune milieu in ovarian cancer.

The main objective of the present investigation was to study the urinary neopterin excretion in the context of the activation of the adaptive cellular immune system at the tumor site. For this purpose, we compared pre-treatment urinary neopterin levels measured in 92 ovarian cancer patients, with intratumoral levels of mRNA transcripts from factors either involved in the adaptive antitumor immune defense (CD3, IFN-γ, IRF-1, IRF-2, SOCS1 and iNOS) or immune tolerance (FoxP3). This study did not reveal an association between urinary neopterin and one of these investigated "on tumor site transcripts". From all the factors reflecting the magnitude of the local adaptive antitumor response, intratumoral IRF-1 expression above the edge of the 25th percentile was found to predict most reliably favorable progression-free (median 34 months vs. 10 months; p < 0.001) and overall (median 52 months vs. 16 months; p < 0.001) survival. In contrast, pre-treatment urinary neopterin excretion above 275 μmol/mol creatinine, which indicates an unspecific activation of the innate immune system, was associated with a very poor overall survival with a median of only 11 months when compared with a median overall survival of 40 months in patients with lower urinary neopterin excretion (p = 0.021). Interestingly, the considerable survival benefit in patients with high IRF-1-expressing cancers was completely abrogated as well for progression-free as for overall survival when urinary neopterin concentrations were found to be concomitantly elevated. These findings demonstrate that in ovarian carcinomas the unspecific "cancer-related inflammation" contributes to a significant subversion of the adaptive antitumor immune defense mounted at the tumor site.