SUMMARY Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling extracellular matrix molecules. Collectively, these findings uncover the heterogeneity of TAM origin and functions, and could provide therapeutic insight for PDAC treatment.

ObjectiveChemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone.MethodsBlood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy.ResultsA systemic increase in CXCR2+ TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2+ TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2+ TAN or CCR2+ TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy.ConclusionDual targeting of CCR2+ TAM and CXCR2+ TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.

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Statement of translational relevanceFOLFIRINOX has demonstrated promising clinical results for patients with pancreatic ductal adenocarcinoma (PDAC). While the immunogenicity of certain chemotherapeutics has been demonstrated, little is known about the impact of neoadjuvant FOLFIRINOX chemotherapy on the immune system in PDAC patients.Here we performed immune phenotype analysis by CyTOF in peripheral blood of untreated patients and FOLFIRINOX-treated patients in the neoadjuvant setting. Distinct immune profiles were observed in FOLFIRINOX-treated patients, including increased Th1 cells and decreased classical monocytes, Th2 cells, and suppressor subsets. Cellular alterations observed in clinical responders to FOLFIRINOX included an increased CD8 T cell frequency and increased CD27 -Tbet + phenotypic fractions in CD4 and CD8 T cells. Our study suggests that neoadjuvant chemotherapy with FOLFIRINOX may enhance functional T cells and downregulate suppressor cells. Taken together, these findings indicate that neoadjuvant FOLFIRINOX may improve immune therapy and clinical outcome in PDAC patients.

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Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.

BACKGROUND To date, work-hour restrictions have not been imposed on attending surgeons in the United States. The purpose of this study was to investigate the impact of working an overnight trauma shift on outcomes of general surgery operations performed the next day by the post-call attending physician. STUDY DESIGN Consecutive patients over a 3.5-year period undergoing elective general surgical procedures were reviewed. Procedures were limited to hernia repairs (inguinal and ventral), cholecystectomies, and intestinal operations. Any operations that were performed the day after the attending surgeon had taken an overnight trauma shift were considered post-call (PC) cases; all other cases were considered nonpost-call (NP). Outcomes from the PC operations were compared with those from the NP operations. RESULTS There were 869 patients identified; 132 operations were performed PC and 737 were NP. The majority of operations included hernia repairs (46%), followed by cholecystectomies (35%), and intestinal procedures (19%). Overall, the PC operations did not differ from the NP operations with respect to complication rate (13.7% vs 13.5%, p = 0.93) or readmission within 30 days (5% vs 6%, p = 0.84). Additionally, multivariable logistic regression failed to identify an association between PC operations and the development of adverse outcomes. Follow-up was obtained for an average of 3 months. CONCLUSIONS Performance of general surgery operations the day after an overnight in-hospital trauma shift did not affect complication rates or readmission rates. At this time, there is no compelling evidence to mandate work-hour restrictions for attending general surgeons.

Prognostic/epidemiologic study, level III; therapeutic study, level IV.