BackgroundLung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer.Methodology/Principal FindingsAntitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect.Conclusions/SignificanceMalaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy.

Group 2 innate lymphoid cells (ILC2s) regulate immunity, inflammation, and tissue homeostasis. Two distinct subsets of ILC2s have been described: steady-state natural ILC2s and inflammatory ILC2s, which are elicited following helminth infection. However, how tissue-specific cues regulate these two subsets of ILC2s and their effector functions remains elusive. Here, we report that interleukin-33 (IL-33) promotes the generation of inflammatory ILC2s (ILC2 INFLAM ) via induction of the enzyme tryptophan hydroxylase 1 (Tph1). Tph1 expression was upregulated in ILC2s upon activation with IL-33 or following helminth infection in an IL-33-dependent manner. Conditional deletion of Tph1 in lymphocytes resulted in selective impairment of ILC2 INFLAM responses and increased susceptibility to helminth infection. Further, RNA sequencing analysis revealed altered gene expression in Tph1 deficient ILC2s including inducible T cell co-stimulator (Icos). Collectively, these data reveal a previously unrecognized function for IL-33, Tph1, and ICOS in promoting inflammatory ILC2 responses and type 2 immunity at mucosal barriers.

Increased expression of Interleukin (IL)-33 has been detected in intestinal samples of patients with ulcerative colitis, a condition associated with increased risk for colon cancer, but its role in the development of colorectal cancer has yet to be fully examined. Here, we investigated the role of epithelial expressed IL-33 during development of intestinal tumors. IL-33 expression was detected in epithelial cells in colorectal cancer specimens and in the Apc Min/+ mice. To better understand the role of epithelial-derived IL-33 in the intestinal tumorigenesis, we generated transgenic mice expressing IL-33 in intestinal epithelial cells (V33 mice). V33 Apc Min/+ mice, resulting from the cross of V33 with Apc Min/+ mice, had increased intestinal tumor burden compared with littermate Apc Min/+ mice. Consistently, Apc Min/+ mice deficient for IL-33 receptor (ST2), had reduced polyp burden. Mechanistically, overexpression of IL-33 promoted expansion of ST2+ regulatory T cells, increased Th2 cytokine milieu, and induced alternatively activated macrophages in the gut. IL-33 promoted marked changes in the expression of antimicrobial peptides, and antibiotic treatment of V33 Apc Min/+ mice abrogated the tumor promoting-effects of IL-33 in the colon. In conclusion, elevated IL-33 signaling increases tumor development in the Apc Min/+ mice.

Six new beta-resorcylic acid lactones (1-6), named paecilomycins A-F, and five known compounds, aigilomycin B (7), zeaenol (8), aigialomycin D (9), aigialomycin F (10), and aigialospirol, were isolated from the mycelial solid culture of Paecilomyces sp. SC0924. Their structures were elucidated by extensive NMR analysis, single-crystal X-ray study, and chemical correlations. Compounds 5 and 10 exhibited antiplasmodial activity against Plasmodium falciparum line 3D7 with IC(50) values of 20.0 and 10.9 nM, respectively, and compounds 5-7 showed moderate activity against the P. falciparum line Dd2.

Interleukin-23 (IL-23) responsive group 3 innate lymphoid cells (ILC3s) have been implicated in immune homeostasis and pathogenesis in the adult, but little is known about their roles in the newborn. Here we show that IL-23 promotes conversion of embryonic intestinal Lin−IL-23R+Thy1+ cells into IL-22-producing Thy1+Sca-1hi ILC3s in vitro. Gut-specific expression of IL-23 also activated and expanded Thy1+Sca-1hi ILC3s, which produced IL-22, IL-17, IFN-γ, and GM-CSF and were distinct from canonical CD4+ lymphoid tissue inducer (LTi) cells. These ILC3s accumulated under the epithelium in intercellular adhesion molecule (ICAM)-1 positive cell aggregates together with neutrophils that disrupted the epithelium, leading to the formation of discrete intestinal erosions, bleeding, and neonatal death. Genetic and antibody depletion of ILC3s rescued the mice from neonatal death. Antibiotic treatment of pregnant mothers and offspring prolonged survival of IL-23 transgenic mice, suggesting a role for the commensal flora on ILC3-induced pathogenesis. Our results reveal a novel role for the IL-23-ILC3s axis in the pathogenesis of neonatal intestinal inflammation.

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The historical paradigm of the deep ocean as a biological 'desert' has shifted to one of a 'rainforest' owing to the isolation of many novel microbes and their associated bioactive compounds. To explore the potential of the bioactive compounds in our marine microbial natural product library, we screened it for the selective cytotoxicity of six different cancer cell lines to human normal lung fibroblast cell line HLF. The crude extract from a marine-derived fungal strain showed notable selectivity against cancer cell lines. For a bioactivity-guided fractionation and purification, a novel cyclopentenone, (-)-(4R *, 5S *)-3-ethyl-4,5-dihydroxycyclopent-2-enone (1, trichoderone), and a known compound with new activity, cholesta-7,22- diene-3 beta,5 alpha,6 beta-triol (2), were identified from a marine Trichoderma sp. that was isolated from the deep sea sediment of the South China Sea. Their structures were determined by NMR and MS data analyses. Trichoderone (1) displayed potent cytotoxicity against a panel of six cancer cell lines, whereas it did not show much cytotoxicity against normal human lung fibroblast cell line HLF even at a concentration of 7.02 mM. The selectivity index (SI) value for 1 was greater than 100. To the best of our knowledge, both compounds were isolated from marine fungi for the first time. They also exhibited bioactivities against HIV protease and Taq DNA polymerase. Optimization of the compounds would shed new light on treating cancer and infectious diseases.