676 Altered circulating myeloid states associated with anti-PD-1 resistance induce T cell paralysis in human biliary cancer

BackgroundAdvanced biliary cancers (ABC) have a poor prognosis and low rates of response to immune checkpoint inhibition (CPI), with overall response rates ranging from 3–13%.1–3 Although suppressive myeloid cells have been proposed as a mechanism of resistance to immunotherapy in general, their relationship to response to CPI is unknown.MethodsWe used multiplexed simultaneous single cell RNA sequencing and cell surface proteomics (CITE-seq) to profile circulating immune cells in ABC patients receiving anti-PD-1 at longitudinal timepoints pre-immunotherapy and on treatment, as well as from healthy donors. We also performed single cell RNA sequencing on resected biliary tumors.ResultsWe identified a novel population of circulating cancer-enriched myeloid cells (CEM) characterized by chemokines and extracellular matrix digestion-related gene expression, which were present pre-treatment. Anti-PD-1 treatment drove the CEMs into two diverging states that were associated with response or resistance to treatment. CEM induced in non-responders constituted over 40% of the circulating myeloid cells and expressed immunosuppressive programs, including the upregulation of suppressive cytokines and chemokines. The frequency of these myeloid cells were correlated with the abundance of SOCS3-expressing CD4+ T cells. These SOCS3+CD4+ T cells also colocalized with tumor-infiltrating myeloid cells that share CEM gene expression signatures in the biliary cancer microenvironment. Moreover, CEM can directly induce SOCS3-expressing T cells, which despite their naïve phenotype are functionally unresponsive. Finally, expression signatures of CEM and of SOCS3+CD4+ T cells are associated with worse survival in a larger cohort of ABC patients.ConclusionsThese results demonstrate the capacity of CEM to induce T cell paralysis as an alternate mode of tumor-mediated immunosuppression. A deeper understanding of immune cell biology in ABC provides insights for developing novel therapeutics that can overcome immunotherapy resistance in biliary cancer as well as other tumor types.Trial RegistrationNCT02703714ReferencesUeno M, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol 2019;4:611–621.Piha-Paul SA, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer 2020.Kim RD, et al. A Phase 2 Multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol 2020;6:888–894.Ethics ApprovalInformed consent was obtained from all patients for participation in the listed trial and for use of blood and tumor samples in research studies.

Impact of the Coronavirus Disease-2019 Pandemic on Pancreaticobiliary Disease Detection and Treatment

The emergency declaration (ED) associated with the coronavirus disease-2019 (COVID-19) pandemic in Japan had a major effect on the management of gastrointestinal endoscopy. We retrospectively compared the number of pancreaticobiliary endoscopies and newly diagnosed pancreaticobiliary cancers before (1 April 2018 to 6 April 2020), during (7 April to 25 May 2020), and after the ED (26 May to 31 July). Multiple comparisons of the three groups were performed with respect to the presence or absence of symptoms and clinical disease stage. There were no significant differences among the three groups (Before/During/After the ED) in the mean number of diagnoses of pancreatic cancer and biliary cancer per month in each period (8.0/7.5/7.5 cases, p = 0.5, and 4.0/3.5/3.0 cases, p = 0.9, respectively). There were no significant differences among the three groups in the number of pancreaticobiliary endoscopies (EUS: endoscopic ultrasonography/ERCP: endoscopic retrograde cholangiopancreatography) per month (67.8/62.5/69.0 cases, p = 0.7 and 89.8/51.5/86.0 cases, p = 0.06, respectively), whereas the number of EUS cases decreased by 42.7% between before and during the ED. There were no significant differences among the three groups in the presence or absence of symptoms at diagnosis or clinical disease stage. There was no significant reduction in the newly diagnosed pancreaticobiliary cancer, even during the ED. The number of ERCP cases was not significantly reduced as a result of urgent procedures, but the number of EUS cases was significantly reduced.

Probiotic-related bacteremia after major hepatectomy for biliary cancer: a report of two cases

Background Probiotics have been reported to be beneficial for the prevention of postoperative complications and are often used during the perioperative period. Among the probiotic-related adverse events, bacteremia is rare. Here, we report two cases of probiotic-related bacteremia after major hepatectomy for biliary cancer. Case presentation 1 A 74-year-old man was referred to our hospital to be treated for gallbladder cancer. Neoadjuvant chemotherapy, two courses of gemcitabine plus S-1 combination therapy, was administered. Extended right hepatectomy with caudate lobectomy, extrahepatic bile duct resection and biliary reconstruction were performed 3 weeks after chemotherapy. Probiotics, Clostridium butyricum (C. butyricum) MIYAIRI 588, were administered 6 days before surgery and continued after surgery. Sepsis of unknown origin occurred 17 days after surgery and developed into septic shock. C. butyricum was detected in blood cultures at postoperative day 26 and 45. After stopping the probiotic agent, C. butyricum was undetectable in the blood cultures. The patient died due to an uncontrollable sepsis 66 days after surgery. Case presentation 2 A 63-year-old man with diabetes mellitus whose past history included total colectomy, papillectomy, and Frey’s operation at the age of 19, 34 and 48, respectively, was referred to our hospital to be treated for perihilar cholangiocarcinoma. Extended left hepatectomy with caudate lobectomy, extrahepatic bile duct resection and reconstruction of bile duct were performed. Probiotics were administered during the perioperative period. Combined probiotics that included lactomin, amylolytic bacillus and C. butyricum, were given before surgery. C. butyricum MIYAIRI 588 was given after surgery. Sepsis occurred 16 days after surgery and developed to respiratory failure 8 days later. Blood culture at postoperative day 25 revealed Enterococcus faecalis and C. butyricum. After the probiotics were stopped at postoperative day 27, C. butyricum was not detected in the blood culture. The general condition improved with intensive care. The patient was transferred to another hospital for rehabilitation at postoperative day 156. Conclusion It should be noted that the administration of probiotics in severe postoperative complications can lead to probiotic-related bacteremia.

Impact of hospital type and surgical volume on outcomes of biliary cancer resection.

e16168 Background: The mainstay of treatment for patients with early-stage biliary cancer (gallbladder or cholangiocarcinoma) is surgical resection. Herein, we evaluated the predictors for biliary cancer resection outcome and association with hospital volume and teaching status. Methods: A national representative cohort of 18485 biliary cancer patients was included for the years 2016 – 2018 from the national inpatient sample database. The study population included patients ≥ 18 years diagnosed with biliary cancer who underwent elective surgical resection (ICD 10). Hospitals were categorized based on teaching status (yes, if ACGME approved residency program, member of the council of teaching hospitals, or with residents to beds ratio of .25 or higher, versus non-teaching); and hospital volume (high if ≥ 20 biliary cancer surgeries performed per year, otherwise low). The primary outcome was biliary resection and the secondary outcomes included post-operative complications, in-hospital mortality, length of stay (< or ≥ 7 days), and health care cost (< or ≥ median) based on hospital teaching status and biliary cancer surgical volume. Association with outcomes was assessed using multivariable logistic regression models adjusted for age, sex, race, household income, service payer, Elixhauser co-morbidity score, hospital volume, teaching status, bed size, location, and region. Results: Out of 18,485 patients hospitalized with biliary cancer, 7,030 patients underwent elective biliary cancer resection during the study period. Patients undergoing resection were likely to have higher than national household median income with Medicare as primary insurance payor. In multivariate adjusted logistic regression models, high volume centers showed significantly lower length of stay (adjusted odds ratio (aOR) 0.73; 95% CI 0.54 - 0.97; p=0.03), and lower in-hospital mortality (aOR 0.28; 95% CI 0.15 - 0.80; p=0.01), but no significant difference in post-operative complications or healthcare cost compared to low volume centers. Surgeries performed in a teaching hospital were associated with decreased risk of post-operative complications (aOR 0.74; 95% CI 0.55 - 1.0; p=0.05), significant decrease in in-hospital mortality (aOR 0.44; 95% CI 0.27 - 0.69; p=0.001), but higher inflation-adjusted healthcare cost (aOR 1.77; 95% CI 1.37-2.26; p<0.001) with no difference in length of stay. Conclusions: Patients who underwent elective biliary cancer surgery at a teaching or high-volume hospital had a significant decrease in their risk of in-hospital mortality. Additionally, surgeries at teaching hospitals were associated with a significantly lower post-operative complication rate compared to similar procedures at a non-teaching hospital, although teaching hospitals did have a significantly higher healthcare cost when adjusted for length of stay.