The cellular and molecular events that drive early innate lympoid cell (ILC) development remain poorly understood. We show that transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILP) that expressed high amounts of TCF-1. EILP lacked efficient T and B lymphocyte potential, but efficiently gave rise to NK cells and all known adult helper-ILC lineages, indicating that they are the earliest identified ILC-committed progenitors. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILP provides a basis to decipher additional signals that specify the ILC fate.

Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1a induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDOexpressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1a/ CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network. Cancer Res; 76(4); 818-30. Ó2016 AACR.

Flexible perovskite solar cells (PSCs) using plastic substrates have become one of the most attractive points in the field of thin-film solar cells. Low-temperature and solution-processable nanoparticles (NPs) enable the fabrication of semiconductor thin films in a simple and low-cost approach to function as charge-selective layers in flexible PSCs. Here, we synthesized phase-pure p-type Cu-doped NiO NPs with good electrical properties, which can be processed to smooth, pinhole-free, and efficient hole transport layers (HTLs) with large-area uniformity over a wide range of film thickness using a room-temperature solution-processing technique. Such a high-quality inorganic HTL allows for the fabrication of flexible PSCs with an active area >1 cm, which have a power conversion efficiency over 15.01% without hysteresis. Moreover, the Cu/NiO NP-based flexible devices also demonstrate excellent air stability and mechanical stability compared to their counterpart fabricated on the pristine NiO films. This work will contribute to the evolution of upscaling flexible PSCs with a simple fabrication process and high device performances.

Tumor-associated macrophages (TAM) have multifaceted roles in tumor development but they have been associated particularly closely with tumor angiogenesis. However, although the accumulation of TAM (M2 phenotype) promotes tumor angiogenesis, the mechanism through which monocytes differentiate to generate TAM is unclear. Here, we report that the mTOR pathway is a critical element in the regulation of monocyte differentiation to TAM. In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference-mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2). Rapamycin caused the monocytes to differentiate into M1 macrophages releasing more interleukin (IL)-12 and less IL-10, whereas TSC2 knockdown caused the monocytes to differentiate into M2 macrophages releasing less IL-12 and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in human umbilical vein endothelial cells cocultured with TSC2-deficient monocytes or rapamycintreated monocytes, respectively. Furthermore, tumor angiogenesis and growth in murine xenografts were promoted or reduced by infusion of hosts with TSC2-deficient or TSC2-overexpressing monocytes, respectively. Finally, in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin on tumors. Our results define the TSC2-mTOR pathway as a key determinant in the differentiation of monocytes into M2 phenotype TAM that promote angiogenesis. Cancer Res; 72(6); 1363-72. Ó2012 AACR.

Background Mutations in the TP53 tumor suppressor gene are common in HNSCC and correlate with radioresistance. Currently, there are no clinically available therapeutic approaches targeting p53 in HNSCC. Here we propose a strategy which uses TP53 mutational status to individualize anti-metabolic strategies for potentiation of radiation toxicity in HNSCC cells. Methods Glycolytic flux and mitochondrial respiration were evaluated in wild-type (wt) and mutant (mut) TP53 HNSCC cell lines. Sensitivity to external beam radiation (XRT) was measured using a clonogenic assay. Results HNSCC cells expressing mutTP53 demonstrated radioresistance compared to HNSCC cells expressing wtTP53. Glycolytic inhibition potentiated radiation toxicity in mutTP53, but not wtTP53 expressing HNSCC cells. The relative sensitivity of mutp53 HNSCC cells to glycolytic inhibition is due to a glycolytic dependence associated with decreased mitochondrial complex II and IV activity. Wild-typeTP53 expressing cells maintain mitochondrial reserves and are relatively insensitive to glycolytic inhibition. Inhibition of respiration using metformin increases glycolytic dependence in wtTP53 expressing cells and potentiates the effects of glycolyic inhibition on radiation toxicity. Conclusion TP53 mutation in HNSCC cells correlates with a metabolic shift away from mitochondrial respiration toward glycolysis resulting in increased sensitivity to the potentiating effects of glycolytic inhibition on radiation toxicity. In contrast, wtTP53 expressing cells require inhibition of both mitochondrial respiration and glycolysis to become sensitized to radiation. One can therefore, use TP53 mutational status as a marker of altered tumor cell metabolism to individualize HNSCC treatment selection of specific targeted metabolic agents that can overcome cellular resistance to radiation therapy.