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Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8 T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8 T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint , a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.

Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that represent one of the few radiologically identifiable precursors to pancreatic ductal adenocarcinoma (PDAC).Though the IPMN-bearing patient population represents a unique opportunity for early detection and interception, current guidelines provide insufficient accuracy in determining which patients should undergo resection versus surveillance, resulting in a sizable fraction of resected IPMNs only harboring low-grade dysplasia, suggesting that there may be overtreatment of this clinical entity. To investigate the transcriptional changes that occur during IPMN progression, we performed spatial transcriptomics using the Nanostring GeoMx on patient samples containing the entire spectrum of IPMN disease including low-grade dysplasia, high-grade dysplasia, and IPMN-derived carcinoma. Single cell RNA sequencing was performed on side branch and main duct IPMN biospecimens. We identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including , and , markers that are enriched in PDAC. We validated and refined this high-risk gene signature by integrating our ST analysis with an external ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). We confirmed the presence of the KRT17+ population using immunofluorescence on a large cohort of patient tissues, revealing a widespread but patchy distribution of KRT17+ cells in histologically low-grade IPMN. Our study demonstrates that KRT17 marks a distinct transcriptional signature in a subpopulation of epithelial cells within histologically low-grade IPMN. This population of cells likely represents a transitional state of histologically low-grade epithelial cells undergoing progression to a higher grade of dysplasia and thus may represent a higher risk of progression to carcinoma.

Specific prosocial behaviors, including volunteering and caregiving, have been linked to better maintenance of cognitive health in older adults. However, limited epidemiologic work has examined the relationship between one’s cognitive-emotional orientation toward prosociality generally and these same health outcomes. This study uses data on 7844 participants from the English Longitudinal Study of Ageing (ELSA) to test the hypothesis that higher versus lower prosociality is associated with higher maintenance of cognitive health in adults 50 years or older. We derived a 9-item prosociality scale using items from well-validated measures of self-reported altruism and collectivism assessed in ELSA. Linear mixed-effects models were used to examine the relationship between this measure and changes in executive function and verbal memory over an 11-year period. Cox proportional hazards models were then used to compare time to dementia based on level of prosociality. Results from both longitudinal and survival analyses suggest that higher prosociality is associated with maintaining better cognitive health even after controlling for sociodemographics (e.g., age, education, wealth) and baseline health characteristics such as depression and cardiovascular disease. Comparing across tertiles, participants with high versus low prosociality had 24% slower decline in verbal memory and 55% slower decline in executive function. This aligned with a 35% reduced hazard of dementia during this same period for those with high vs. low prosociality. These results suggests that prosociality, beyond formal volunteering, is an important modifiable risk factor for improving later life cognitive function on an individual and population level and should therefore be further examined.