Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade.

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.

Endoscopic ultrasound assessment of lesions of the ampulla of Vater is of particular value in low-grade dysplasia.

BACKGROUND: The accurate diagnosis of dysplasia or carcinoma within ampullary lesions can be difficult, but, when possible, identifies patients who require endoscopic or surgical resection, respectively. The role of endoscopic ultrasound (EUS) in diagnosing these lesions and the degree of dysplasia is unclear. METHODS: Patients with lesions of the ampulla were identified over 5 years. Patients who did not undergo EUS were compared with those who did. RESULTS: A total of 27 of 58 (47%) patients were investigated with EUS. Pretreatment diagnoses were correct in 93% of the EUS group vs. 78% of the no-EUS group. Rates of diagnostic accuracy in low-grade dysplasia (LGD), high-grade dysplasia (HGD) and adenocarcinoma (ADC) were 72%, 20% and 96%, respectively, in the no-EUS group, and 93%, 50% and 100%, respectively, in the EUS group. Every diagnosis of LGD in the EUS group was correct, whereas these diagnoses accounted for the majority of errors (eight of 13) in the no-EUS group. High-grade dysplasia was frequently misdiagnosed. More patients were treated by endoscopic resection in the EUS group (12 of 27 vs. five of 31; P= 0.025). CONCLUSIONS: Endoscopic ultrasound increases the accuracy of preoperative diagnosis of ampullary lesions and is particularly useful in patients with LGD because it permits safe endoscopic management. Patients with HGD must be reviewed carefully and considered for pancreatoduodenectomy.

Role of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of solid pancreatic and peripancreatic lesions: is onsite cytopathology necessary?

OBJECTIVES: The reported median diagnostic yield from endoscopic ultrasound (EUS) fine-needle aspiration (FNA) cytology is 78% (range 39-93%). The aim of this study is to describe a single-centre experience in the diagnostic work-up of solid pancreatic and peripancreatic masses without the benefit of an onsite cytopathologist. METHODS: In a consecutive series of 429 EUS examinations performed over a 12-month period by a single operator, 108 were on non-cystic pancreatic or biliary lesions. Data were collected prospectively and the accuracy of FNA was assessed retrospectively using either surgery or repeat imaging as the benchmark in the presence or absence of malignancy. RESULTS: Of the 108 FNAs, 102 (94%) were diagnostic, four were falsely negative (FN) and two were atypical and considered equivocal. There were 78 pancreatic lesions, of which 65 were true positives (TP), 11 true negatives (TN) and two FN, giving an overall accuracy of 97% (76/78). Of nine periampullary lesions, two were TP, six were TN and one was FN, giving an overall accuracy of 89% (8/9). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of EUS-FNA for pancreatic and periampullary lesions combined were 96%, 100%, 100% [95% confidence interval (CI) 95-100%], 85% (95% CI 62-97%) and 97%, respectively. There were 21 bile duct lesions, of which 10 were TP, eight TN, two atypical and one FN, giving an overall accuracy of 86% (18/21). The sensitivity, specificity, PPV, NPV and accuracy of EUS-FNA for biliary lesions were 91%, 100%, 100% (95% CI 69-100%), 91% (95% CI 59-100%) and 95%, respectively. CONCLUSIONS: The diagnostic accuracy of EUS-FNA for pancreatic lesions in our series was 97% and the PPV for the three subgroups of lesion type was 100%; these figures are comparable with the best rates reported in the literature, despite the absence of onsite cytopathology. These rates are potentially a direct result of high-volume practice, dedicated endosonography and cytopathology. These results show that it is possible to achieve high rates of accuracy in places where logistical issues make it impossible to maintain a cytopathologist in the endoscopy suite. In addition, our results contribute to the limited, collective global experience on the effectiveness of EUS-FNA in periampullary and biliary lesions.