•Regulation of CD73 expression in cancer cells.•Regulation of CD73 on host cells.•Prognostic impact of CD73 in cancer.•Overview of CD73 targeting agents in clinical trials.
The ectonucleotidases CD39 ...and CD73 are cell surface enzymes that catabolize the breakdown of extracellular ATP into adenosine. As such, they constitute critical components of the extracellular purinergic pathway and play important roles in maintaining tissue and immune homeostasis. With the coming of age of cancer immunotherapy, ectonucleotidases and adenosine receptors have emerged as novel therapeutic targets to enhance antitumor immune responses. With early-phase clinical trials showing promising results, it is becoming increasingly important to decipher the distinct mechanisms-of-action of adenosine-targeting agents, identify patients that will benefit from these agents and rationally develop novel synergistic combinations. Given the broad expression of ectonucleotidases and adenosine receptors, a better understanding of cell-specific roles will also be key for successful implementation of this new generation of immuno-oncology therapeutics. We here review the latest studies on the roles of CD73 and adenosine in cancer with a focus on cell-specific function. We also discuss ongoing clinical trials and future avenues for adenosine-targeting agents.
After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological ...growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication.
From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes.
The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3
T cell infiltration, a phenotype associated with a short median RFS of 7.9 months.
Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.
Finding a noninvasive radiomic surrogate of tumor immune features could help identify patients more likely to respond to novel immune checkpoint inhibitors. Particularly, CD73 is an ectonucleotidase ...that catalyzes the breakdown of extracellular AMP into immunosuppressive adenosine, which can be blocked by therapeutic antibodies. High CD73 expression in colorectal cancer liver metastasis (CRLM) resected with curative intent is associated with early recurrence and shorter patient survival. The aim of this study was hence to evaluate whether machine learning analysis of preoperative liver CT-scan could estimate high vs low CD73 expression in CRLM and whether such radiomic score would have a prognostic significance.
We trained an Attentive Interpretable Tabular Learning (TabNet) model to predict, from preoperative CT images, stratified expression levels of CD73 (CD73
vs. CD73
) assessed by immunofluorescence (IF) on tissue microarrays. Radiomic features were extracted from 160 segmented CRLM of 122 patients with matched IF data, preprocessed and used to train the predictive model. We applied a five-fold cross-validation and validated the performance on a hold-out test set.
TabNet provided areas under the receiver operating characteristic curve of 0.95 (95% CI 0.87 to 1.0) and 0.79 (0.65 to 0.92) on the training and hold-out test sets respectively, and outperformed other machine learning models. The TabNet-derived score, termed rad-CD73, was positively correlated with CD73 histological expression in matched CRLM (Spearman's ρ = 0.6004; P < 0.0001). The median time to recurrence (TTR) and disease-specific survival (DSS) after CRLM resection in rad-CD73
vs rad-CD73
patients was 13.0 vs 23.6 months (P = 0.0098) and 53.4 vs 126.0 months (P = 0.0222), respectively. The prognostic value of rad-CD73 was independent of the standard clinical risk score, for both TTR (HR = 2.11, 95% CI 1.30 to 3.45, P < 0.005) and DSS (HR = 1.88, 95% CI 1.11 to 3.18, P = 0.020).
Our findings reveal promising results for non-invasive CT-scan-based prediction of CD73 expression in CRLM and warrant further validation as to whether rad-CD73 could assist oncologists as a biomarker of prognosis and response to immunotherapies targeting the adenosine pathway.
Minimally invasive surgery is increasingly preferred for left-sided pancreatic resections. The SIMPLR study aims to compare open, laparoscopic, and robotic approaches using propensity score matching ...analysis.
This study included 258 patients with tumors of the left side of the pancreas who underwent surgery between 2016 and 2020 at three high-volume centers. The patients were divided into three groups based on their surgical approach and matched in a 1:1 ratio.
The open group had significantly higher estimated blood loss (620 mL vs. 320 mL,
< 0.001), longer operative time (273 vs. 216 min,
= 0.003), and longer hospital stays (16.9 vs. 6.81 days,
< 0.001) compared to the laparoscopic group. There was no difference in lymph node yield or resection status. When comparing open and robotic groups, the robotic procedures yielded a higher number of lymph nodes (24.9 vs. 15.2,
= 0.011) without being significantly longer. The laparoscopic group had a shorter operative time (210 vs. 340 min,
< 0.001), shorter ICU stays (0.63 vs. 1.64 days,
< 0.001), and shorter hospital stays (6.61 vs. 11.8 days,
< 0.001) when compared to the robotic group. There was no difference in morbidity or mortality between the three techniques.
The laparoscopic approach exhibits short-term benefits. The three techniques are equivalent in terms of oncological safety, morbidity, and mortality.
Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a ...new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.
In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to ...preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3
+
T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months,
p
= .0018) and disease-specific survival (DSS) (not reached vs. 48 months,
p
= .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.
Chronic liver disease (CLD) remains a global health issue associated with a significant disease burden. Liver fibrosis, a hallmark of CLD, is characterised by the activation of hepatic stellate cells ...(HSCs) that gain profibrotic characteristics including increased production of extracellular matrix protein. Currently, no antifibrotic therapies are available clinically, in part because of the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for antifibrotic drug development.
Small interfering RNA-mediated knockdown of GPR176 was used to assess the in vitro function of GPR176 in HSCs and in precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed using the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knockout mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets.
We identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knockdown of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of GPR176 did not influence liver homeostasis, but Gpr176-/- mice developed less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression was correlated with in vitro HSC activation and with fibrosis stage in patients with CLD.
GPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific antifibrotic candidate to treat CLD.
The lack of effective antifibrotic drugs is partly attributed to the insufficient knowledge about the mechanisms involved in the development of liver fibrosis. We demonstrate that the G-protein coupled receptor GPR176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens new avenues for the development of targeted interventions.
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•GPR176 is highly enriched in activated mouse HSCs in different models of chronic liver injury.•GPR176 shows early and sustained induction during HSC activation, preceding the expression of canonical myofibroblast markers.•Targeted Gpr176 mRNA in vitro knockdown and in vivo knockout results in downregulation of fibrotic markers.•GPR176 expression in human livers correlates with fibrosis stage, indicating its relevance to human liver disease.
models of human liver disease often fail to mimic the complex 3D structures and cellular organizations found
. Precision cut liver slices (PCLS) retain the complex physiological architecture of the ...native liver and therefore could be an exceptional
liver model. However, the production of PCLS induces a spontaneous culture-induced fibrogenic reaction, limiting the application of PCLS to anti-fibrotic compounds. Our aim was to improve PCLS cultures to allow compound-induced fibrosis induction. Hepatotoxicity in PCLS cultures was analyzed by lactate dehydrogenase leakage and albumin secretion, while fibrogenesis was analyzed by qRT-PCR and western blot for hepatic stellate cell (HSC) activation markers and collagen 6 secretion by enzyme-linked immunosorbent assays (ELISA). We demonstrate that supplementation of 3 mm mouse PCLS cultures with valproate strongly reduces fibrosis and improves cell viability in our PCLS cultures for up to 5 days. Fibrogenesis can still be induced both directly and indirectly through exposure to TGFβ and the hepatotoxin acetaminophen, respectively. Finally, human PCLS cultures showed similar but less robust results. In conclusion, we optimized PCLS cultures to allow for drug-induced liver fibrosis modeling.
Abstract
Background and study aims
Gastric outlet obstruction (GOO) is traditionally managed with surgical gastroenterostomy (surgical-GE) and enteral stenting (ES). Endoscopic ultrasound-guided ...gastroenterostomy (EUS-GE) is now a third option. Large studies assessing their relative risks and benefits with adequate follow-up are lacking. We conducted a comparative analysis of patients who underwent EUS-GE, ES, or surgical-GE for GOO.
Patients and methods
In this retrospective comparative cohort study, consecutive patients presenting with GOO who underwent EUS-GE, ES, or surgical-GE at two academic institutions were reviewed and independently cross-edited to ensure accurate reporting. The primary outcome was need for reintervention. Secondary outcomes were technical and clinical success, length of hospital stay (LOS), and adverse events (AEs).
Results
A total of 436 patients (232 EUS-GE, 131 ES, 73 surgical-GE) were included. The median duration of follow-up of the entire cohort was 185.5 days (interquartile range 55.25–454.25 days). The rate of reintervention in the EUS-GE group was lower than in the ES and surgical-GE groups (0.9 %, 12.2 %, and 13.7 %,
P
< 0.0001). Technical success was achieved in 98.3 %, 99.2 %, and 100 % (
P
= 0.58), and clinical success was achieved in 98.3 %, 91.6 %, and 90.4 % (
P
< 0.0001) in the EUS-GE, ES, and surgical-GE groups, respectively. The EUS-GE group had a shorter LOS (2 days vs. 3 days vs. 5 days,
P
< 0.0001) and a lower AE rate than the ES and surgical-GE groups (8.6 % vs. 38.9 % vs. 27.4 %,
P
< 0.0001).
Conclusion
This large cohort study demonstrates the safety and palliation durability of EUS-GE as an alternative strategy for GOO palliation in select patients.
Abstract
Objective: Following cardiac surgery, a great variety in intensive care unit (ICU) stay is observed, making it often difficult to adequately predict ICU stay preoperatively. Therefore, a ...study was conducted to investigate, which preoperative variables are independent risk factors for a prolonged ICU stay and whether a patient's risk of experiencing an extended ICU stay can be estimated from these predictors. Methods: The records of 1566 consecutive adult patients who underwent cardiac surgery at our institution were analysed retrospectively over a 2-year period. Procedures included in the analyses were coronary artery bypass grafting, valve replacement or repair, ascending and aortic arch surgery, ventricular rupture and aneurysm repair, septal myectomy and cardiac tumour surgery. For this patient group, ICU stay was registered and 57 preoperative variables were collected for analysis. Descriptives and log-rank tests were calculated and Kaplan-Meier curves drawn for all variables. Significant predictors in the univariate analyses were included in a Cox proportional hazards model. The definitive model was validated on an independent sample of 395 consecutive adult patients who underwent cardiac surgery at our institution over an additional 6-month period. In this patient group, the accuracy and discriminative abilities of the model were evaluated. Results: Twelve independent preoperative predictors of prolonged ICU stay were identified: age at surgery > 75 years, female gender, dyspnoea status > New York Heart Association class II (NYHA II), unstable symptoms, impaired kidney function (estimated glomerular filtration rate (eGFR) ≪ 60 ml min−1), extracardiac arterial disease, presence of arrhythmias, mitral insufficiency > colour flow mapping (CFM) grade II, inotropic support, intra-aortic balloon pumping (IABP), non-elective procedures and aortic surgery. The individual effect of every predictor on ICU stay was quantified and inserted into a mathematical algorithm (called the Morbidity Defining Cardiosurgical (MDC) index), making it possible to calculate a patient's risk of having an extended ICU stay. The model showed very good calibration and very good to excellent discriminative ability in predicting ICU stay >2, >5 and >7 days (C-statistic of 0.78; 0.82 and 0.85, respectively). Conclusions: Twelve independent preoperative risk factors for a prolonged ICU stay following cardiac surgery were identified and constructed into a proportional hazards model. Using this risk model, one can predict whether a patient will have a prolonged ICU stay or not.
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