CD4⁺ helper T cells can differentiate into several possible fates including: Th1, Th2, T regulatory, and Th17 cells. Although, cytokine production by non-T cells is an important factor in helper T cell differentiation, a characteristic feature of both Th1 and Th2 lineages is their ability to secrete cytokines that promote their respective differentiation. However, cytokines produced by T cells that help to sustain Th17 cells have not yet been identified. Here we show that IL-21 is a product of Th17 cells, which is induced in a Stat3-dependent manner. Additionally, Stat3 can directly bind the Il21 promoter. IL-21 also induces IL-17 production and expression of the transcription factor, RORγt. Furthermore, generation of Th17 cells in the conventional manner is attenuated by blocking IL-21. IL-21 is known to activate Stat3 and its ability to induce Th17 differentiation is abrogated in the absence of Stat3. These data argue that IL-21 serves as an autocrine factor secreted by Th17 cells that promotes or sustains Th17 lineage commitment.

CD4+ helper T (Th) cells play a crucial role in the delicate balance between host defense and autoimmune disease. Two important populations of helper T cells are the proinflammatory, interleukin-17 (IL-17)–producing (Th17) cells and the anti-inflammatory forkhead box P3–positive (FoxP3+) T regulatory (Treg) cells. Here we show that all-trans retinoic acid (ATRA) and other agonists of the retinoic acid receptor alpha (RARα) inhibit the formation of Th17 cells and promote FoxP3 expression. Conversely, inhibition of retinoic acid signaling constrains transforming growth factor beta (TGF-β1) induction of FoxP3. The effect of ATRA is mediated independently of IL-2, signal transducer and activator of transcription 5 (Stat5) and Stat3, representing a novel mechanism for the induction of FoxP3 in CD4 T cells. As previous studies have shown that vitamin A derivatives are protective in animal models of autoimmune disease, the current data suggest a previously unrecognized role for RARα in the regulation of CD4+ T-cell differentiation and provide a mechanism for the anti-inflammatory effects of retinoic acid.

Background: Enhanced recovery after surgery (ERAS) programs are multimodal care pathways designed to minimize the physiological and psychological impact of surgery for patients. Increased compliance with ERAS guidelines is associated with improved patient outcomes across surgical types. As ERAS programs have proliferated, an unintentional effect has been significant variation in how ERAS‐related studies are reported in the literature.Methods: To improve the quality of ERAS reporting, ERAS^® USA and the ERAS^® Society launched an effort to create an instrument to assist authors in manuscript preparation. Criteria to include were selected by a combination of literature review and expert opinion. The final checklist was refined by group consensus.Results: The Societies present the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. The tool contains 20 items including best practices for reporting clinical pathways, compliance auditing, and formatting guidelines.Conclusions: The RECOvER Checklist is intended to provide a standardized framework for the reporting of ERAS‐related studies. The checklist can also assist reviewers in evaluating the quality of ERAS‐related manuscripts. Authors are encouraged to include the RECOvER Checklist when submitting ERAS‐related studies to peer‐reviewed journals.

Early detection of ovarian cancer could reduce mortality by 10% to 30%. Effective screening requires high sensitivity (>75%) and extremely high specificity (99.7%). Clinical trials suggest the best specificity is achieved with 2-stage strategies in which increasing serum CA125 level triggers transvaginal sonography to detect a malignant pelvic mass, although evidence for such approaches improving overall survival has been limited. Screening may be improved by combining CA125 with novel biomarkers, such as autoantibodies, circulating tumor DNA, or microRNAs. In order to detect premetastatic ovarian cancers originating in the distal fallopian tube, more sensitive approaches to diagnostic imaging are required.

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. Significance: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.