Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer.

Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab, we transcriptionally profiled 358,067 single cells to identify evolving multicellular tumor microenvironment (TME) networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab, we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in antitumor immune hub formation could expand the portion of patients benefiting from anti-PD-1 approaches. SIGNIFICANCE: The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.

A systematic review of HIV screening programs conducted in pediatric emergency departments in the United States.

BACKGROUND: We conducted a systematic review of studies published in peer-reviewed journals on HIV screening programs conducted in pediatric emergency departments (PEDs) in the United States (US) with the objective of describing the methods, testing yields and challenges in these programs. METHODS: We searched for full-text, English-language, original research articles focused on the conduct, development, initiation or implementation of any HIV screening program in a US PED through eight online databases (Pubmed (MEDLINE), Scopus, Embase, Cochrane, Web of Science, CINAHL, PsycInfo and Google Scholar) from their inception through July 2020. We also searched for articles on the websites of thirteen emergency medicine journals, 24 pediatric and adolescent health journals, and ten HIV research journals, and using the references of articles found through these searches. Data on HIV testing program components and yield of testing was extracted by one investigator independently and verified by a second investigator. Each program was summarized and critiqued. RESULTS: Of the eight articles that met inclusion criteria, most involved descriptions of their HIV testing program, except for one that was focused on quality improvement of their program. Five described an opt-in and three an opt-out approach to HIV screening. Programs differed greatly by type of HIV test utilized and who initiated or performed testing. There were large variations in the percentage of patients offered (4.0% to 96.7%) and accepting (42.7% to 86.7%) HIV testing, and HIV seropositivity in the studies ranged from 0 to 0.6%. Five of the eight studies reported an HIV seropositivity greater than 0.1%, above Centers for Disease Control and Prevention recommended threshold for testing in a healthcare setting. CONCLUSIONS: The studies illustrate opportunities to further optimize the integration of HIV screening programs within US PEDs and reduce barriers to testing, improve efficiency of testing results and increase effectiveness of programs to identify cases. Future research should focus on advancing the methodology of screening programs beyond feasibility studies as well as conducting investigations on their implementation and longer-term sustainability.

Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells.

The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by stem cells injected into infarcted hearts can induce recovery through the delivery of stem-cell-specific miRNAs. However, the retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes derived from induced pluripotent stem (iPS) cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased cardiomyocyte apoptosis 24 hours after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that the EVs are enriched with cardiac-specific miRNAs known to modulate cardiomyocyte-specific processes. The extended delivery of EVs secreted from iPS-cell-derived cardiomyocytes into the heart may help understand heart recovery and treat heart injury.