Citations

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745

Abstract Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor β. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17β-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

SummaryBackgroundProton pump inhibitors (PPI) are inconsistently associated with osteoporotic fractures. Barrett's oesophagus (BO) patients are treated with high PPI doses for prolonged periods, but there are limited data on the incidence of osteoporosis and fractures in this group pf patients.AimTo estimate the incidence of (and risk factors for) low bone mass (osteoporosis and/or osteopenia) related fractures in a population‐based BO cohort.MethodsAll subjects with BO and a diagnosis of osteoporosis and fractures were identified using Rochester Epidemiology Project resources. The incidence rates of all and osteoporotic fractures in these subjects were compared to an age‐ and gender similar population in Olmsted County to determine standardised incidence ratios (SIR). Predictors were assessed using Cox proportional hazards models.ResultsFive hundred and twenty‐one patients were included (median [IQR] age 61 [52, 72] years; 398 [76%] men) of whom 113 (21.7%) had fractures, and 46 (8.8%) had osteoporotic fractures. The incidence of all fractures and osteoporotic fractures was comparable to that of an age‐ and gender‐matched population (SIR 1.09; 95% CI 0.92‐1.29: SIR 1.05; 95% CI 0.85‐1.29). PPI use, dose or duration of use was not associated with osteoporotic fracture risk (HR 0.87; 95% CI 0.12‐6.39). Independent risk factors for osteoporotic fractures included older age, female gender and higher co‐morbidity index.ConclusionsThe incidence of osteoporotic fractures was not increased in BO patients compared to the general population. In addition, PPI use was not associated with increased fracture risk regardless of the duration of therapy or dose.

Summary Interleukin ( IL )‐33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL ‐33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL ‐33 and group 2 innate lymphoid cells ( ILC 2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL ‐33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL ‐33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL ‐33 and ILC 2 levels are elevated in patients with allergic airway diseases suggest that IL ‐33 plays an important role in the pathogenesis of these diseases. IL ‐33 and ILC 2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL ‐33 and discussed the roles of the IL ‐33 in regulating airway immune responses and allergic airway diseases.

BACKGROUNDPrior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists.METHODSThe authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan‐Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM‐specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses.RESULTSA total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65‐0.99) but not HM‐specific mortality (HR, 0.77 [95% CI, 0.53‐1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70‐1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59‐1.01) and 0.46 (95% CI, 0.24‐0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation.CONCLUSIONSThe current post hoc analysis of data from a large and well‐executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168–4177. © 2017 American Cancer Society.

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]

2 Background: The CA184-043 phase 3 study did not reach statistical significance for its primary endpoint of OS (HR=0.85, p=0.053). However, antitumor activity was observed in other efficacy endpoints, including progression-free survival. Prespecified subset analyses were performed to understand if any prognostic features may identify mCRPC patients (pts) more likely to benefit from Ipi treatment. Methods: 799 pts were randomized to receive a single dose of radiotherapy (RT) followed by either Ipi (N=399) or Pbo (N=400). Prespecified subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Prespecified subset analyses suggested that Ipi may be more active in pts with favorable prognostic factors, including no visceral disease, alkaline phosphatase <1.5 ULN, and hemoglobin ≥11 g/dL (Table). The safety profile in this study was consistent with previous reports of Ipi. Conclusions: Based on these subset analyses, Ipi added to RT appears to have greater activity than RT alone in pts with a favorable prognostic profile. These results support continued investigation of Ipi in the ongoing CA184-095 study in chemotherapy-naive mCRPC pts. Clinical trial information: NCT00861614. [Table: see text]