Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

Conversations About Children When an Important Adult Is at End of Life: An Audit.

PURPOSE: Health and social care professionals report it challenging to have conversations with families when an important adult in the life of a child is at end of life, often feeling this aspect of care is the responsibility of other colleagues. This study aimed to understand professionals' perceived role in family-centered conversations as part of routine care at end of life, and how to promote this element of care in clinical practice. METHODS: An audit was completed with 116 professionals who work in palliative care including doctors and nurses that attended a 2-day virtual congress. RESULTS: Professionals (73.2%) felt confident about starting a conversation with adult patients at end of life about important children. However, enquiring about relationships with children was largely dependent on the age of the patient. 64.7% of respondents reported signposting families to websites and services that provide family support. Most professionals (76.7%) wanted training to equip them with the skills and confidence to having family-centered conversations at end of life, with videos demonstrating how to provide these elements of care the most preferred option. CONCLUSIONS: Short training resources should be developed to equip professionals with the necessary skills toward having conversations about children with patients and relatives in clinical appointments. There is a need for professionals to ask every patient about important relationships with children.

Cancer Cell Invasion of Mammary Organoids with Basal-In Phenotype.

This paper describes mammary organoids with a basal-in phenotype where the basement membrane is located on the interior surface of the organoid. A key materials consideration to induce this basal-in phenotype is the use of a minimal gel scaffold that the epithelial cells self-assemble around and encapsulate. When MDA-MB-231 breast cancer cells are co-cultured with epithelial cells from day 0 under these conditions, cells self-organize into patterns with distinct cancer cell populations both inside and at the periphery of the epithelial organoid. In another type of experiment, the robust formation of the basement membrane on the epithelial organoid interior enables convenient studies of MDA-MB-231 invasion in a tumor progression-relevant direction relative to epithelial cell-basement membrane positioning. That is, the study of cancer invasion through the epithelium first, followed by the basement membrane to the basal side, is realized in an experimentally convenient manner where the cancer cells are simply seeded on the outside of preformed organoids, and their invasion into the organoid is monitored. Interestingly, invasion is more prominent when tumor cells are added to day 7 organoids with less developed basement membranes compared to day 16 organoids with more defined ones.

The academic health center in complex humanitarian emergencies: lessons learned from the 2010 Haiti earthquake.

On January 12, 2010, a 7.0-magnitude earthquake struck Haiti. The event disrupted infrastructure and was marked by extreme morbidity and mortality. The global response to the disaster was rapid and immense, comprising multiple actors-including academic health centers (AHCs)-that provided assistance in the field and from home. The authors retrospectively examine the multidisciplinary approach that the University of Chicago Medicine (UCM) applied to postearthquake Haiti, which included the application of institutional structure and strategy, systematic deployment of teams tailored to evolving needs, and the actual response and recovery. The university mobilized significant human and material resources for deployment within 48 hours and sustained the effort for over four months. In partnership with international and local nongovernmental organizations as well as other AHCs, the UCM operated one of the largest and more efficient acute field hospitals in the country. The UCM's efforts in postearthquake Haiti provide insight into the role AHCs can play, including their strengths and limitations, in complex disasters. AHCs can provide necessary intellectual and material resources as well as technical expertise, but the cost and speed required for responding to an emergency, and ongoing domestic responsibilities, may limit the response of a large university and hospital system. The authors describe the strong institutional backing, the detailed predeployment planning and logistical support UCM provided, the engagement of faculty and staff who had previous experience in complex humanitarian emergencies, and the help of volunteers fluent in the local language which, together, made UCM's mission in postearthquake Haiti successful.