We have shown that KRAS-TP53 genomic co-alteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS-TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-K-rasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms trafficking and functional dynamics of neutrophils to overcome T-cell exclusion, and controls tumor growth in a T-cell-dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor-cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembraneTNF-TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell-neutrophil crosstalk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC.

Background There is evidence of racial disparity in the long-term weight loss outcomes of bariatric surgery. However, there has been a more limited evaluation of the impact of race on immediate perioperative outcomes. The aim of this study was to compare 30-day postoperative outcomes among different races. Study Design The 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was queried to identify patients aged ≥ 18 and body mass index ≥ 35 who underwent primary laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) with known information on race. We then evaluated the effect of five different races on four different 30-day outcomes. Results Of the total 106,932 patients (79.5% White, 19.3% African American (AA), 0.5% Asian, 0.4% American Indian or Alaska Native, 0.3% Native Hawaiian or other Pacific Islander), 30-day rates of postoperative complication, readmission, reintervention, and reoperation were 6, 3.8, 1.3, and 1.2%, respectively. After controlling for other covariates in multivariate logistic regression and selecting White as reference, AA was the only race associated with a higher risk of postoperative complications (odds ratio [OR] 1.13; confidence interval [CI] 1.06-1.2) and readmissions (OR 1.47; CI 1.3-1.6). AA and American Indian or Alaska Native were also associated with higher re-interventions (OR 1.31; CI 1.15-1.51 and OR 2.11; CI 1.03-4.34). Furthermore, AA was associated with lower 30-day reoperations (OR 0.83; CI 0.7-0.9). Conclusion This study found significant racial differences in short-term outcomes following bariatric surgery. Factors underlying these disparities are unclear and warrant further investigation.

Background Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers. Methods In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer. Results The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases. Conclusions Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.

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