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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Pol6, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR- deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated [CD8.sup.+] T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment., Introduction Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy typically diagnosed at an advanced stage and is minimally responsive to chemotherapy and ionizing radiation. Over the past decade, large-scale [...]

The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity., Introduction Gut microbiota represent the most abundant and diverse collection of commensal organisms in the body (1). The intestinal microbiome plays a fundamental role in shaping the host immune system [...]

A study of pancreatic ductal adenocarcinoma shows that cancer cell proliferation is associated with increased expression of proteins that control programmed necrotic cell death and suppress the adaptive immune system. Cell proliferation in pancreatic ductal adenocarcinoma George Miller and colleagues have investigated the role of programmed necrosis in pancreatic ductal adenocarcinoma (PDA). They observe upregulation of the necrosome factors CXCL1 and Mincle, and this correlates with proliferation of the cancer cells. Furthermore, necroptosis induces signalling pathways that lead to suppression of the adaptive immune system, reinforcing the development of PDA. Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis.sup.1. Conversely, cancer cells often disrupt apoptosis to survive.sup.2,3. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs.sup.4,5. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression., Author(s): Lena Seifert [sup.1] , Gregor Werba [sup.1] , Shaun Tiwari [sup.1] , Nancy Ngoc Giao Ly [sup.1] , Sara Alothman [sup.1] , Dalia Alqunaibit [sup.1] , Antonina Avanzi [sup.1] [...]

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development. [ABSTRACT FROM AUTHOR]

Background Video-assisted thoracoscopic surgery (VATS) offers reduced morbidity compared with open thoracotomy (OT) for pulmonary surgery. The use of VATS over time has increased, but at a modest rate in civilian populations. This study examines temporal trends in VATS use and compares outcomes between VATS and OT in the Veterans Health Administration (VHA). Methods Patients who underwent pulmonary surgery (wedge or segmental resection, lobectomy, or pneumonectomy) at Veterans Affairs centers from 2008 to 2018 were retrospectively identified using the Veterans Affairs Surgical Quality Improvement Project database. The cohort was divided into OT and VATS and propensity score matched, taking into account the type of pulmonary resection, preoperative diagnosis, and comorbidities. Thirty-day postoperative outcomes were compared. The prevalence of VATS use and respective complications over time was also analyzed. Results A total of 16,895 patients were identified, with 5,748 per group after propensity matching. VATS had significantly lower rates of morbidity and a 2-day reduction in hospital stay. Whereas 76% of lung resections were performed open in 2008, nearly 70% of procedures were performed using VATS in 2018. While VATS was associated with an 8% lower rate of major complications compared with thoracotomy in 2008, patients undergoing VATS lung resection in 2018 had a 58% lower rate of complications (p < 0.001). Conclusions VATS utilization at VHA centers has become the predominant technique used for pulmonary surgeries over time. OT patients had more complications and longer hospital stays compared with VATS. Over the study period, VATS patients had increasingly lower complication rates compared with open surgery. [ABSTRACT FROM AUTHOR]

Objective: Mediastinal masses are commonly encountered by the thoracic surgeon. Few studies have reported on the frequency and characteristics of symptoms at presentation. The primary objective of this study is to determine how often patients present with symptoms from a mediastinal mass. The secondary objective is to determine if the presence of symptoms has an effect on outcomes after surgery.Methods: A retrospective review of an institutional database was performed. All patients who underwent surgical resection of a mediastinal mass from 2013 to 2019 were included in the analysis. Medical records were reviewed for the presence or absence of symptoms preoperatively, and these cohorts were compared. Multivariable analysis was performed, adjusting for clinical variables to assess for differences between these cohorts.Results: 70 patients underwent surgery for a mediastinal mass. The average age was 49.2 years, and 46 patients (65.7%) presented with symptoms. There were no significant differences in demographics between the symptomatic and asymptomatic groups. The most common symptom was dyspnea in 18 patients (22%), followed by chest pain (15 patients, 19%) and dysphagia (8 patients, 10%). When comparing symptomatic and asymptomatic patients, symptomatic patients had a larger tumor size (5.8 cm vs 3.8 cm, P = .04) and a longer length of stay (2.0 days vs 1.2 days, P = .02).Conclusions: The majority of patients with mediastinal masses present with symptoms, with the most common symptom being dyspnea. Symptomatic patients are more likely to have a larger tumor and tend to have a longer length of hospital stay postoperatively compared to asymptomatic patients. [ABSTRACT FROM AUTHOR]