T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.

Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all- retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti-VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti-VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types. Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment. http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg .

Sarcoidosis, a chronic, inflammatory disease that affects various different organs, is characterized by noncaseating epitheloid granulomas. This systemic inflammatory process is associated with an increased risk of cancer. Several cases of sarcoidosis that mimic metastatic tumor progression in radiological findings have been reported so far. However, there are also cases that have presented a coexistence of sarcoidosis and metastasis, which have caused a diagnostic and therapeutic dilemma. Due to inadequate current therapies, a reliable differentiation between benign and malignant lesions is crucial. This review focuses on the residual risk of the coexistence of metastases within radiological suspicious lesions in patients with a history of solid tumors and sarcoidosis, as well as immunological findings, in order to explain the potential associations. Sarcoidosis has the potential to promote metastasis as it includes tumor-promoting and immune-regulating cell subsets. Notably, myeloid derived suppressor cells may serve a pivotal role in metastatic progression in patients with sarcoidosis. In addition, the present review also evaluates the potential novel diagnostic approaches, which may be able to differentiate between metastatic lesions and sarcoidosis. The risk of coexistent metastasis in sarcoidosis lesions must be considered by clinical practitioners, and a multidisciplinary approach may be required to avoid misdiagnosis and the subsequent unnecessary surgery or insufficient treatments.

Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model in vivo. Using Raf-BxB transgenic mice that spontaneously develop NSCLCs, we demonstrated that infection with low-pathogenic IAV leads to rapid and efficient oncolysis, eliminating 70% of the initial tumor mass. Interestingly, IAV infection of Raf-BxB mice caused a functional reversion of immunosuppressed tumor-associated lung macrophages into a M1-like pro-inflammatory active phenotype that additionally supported virus-induced oncolysis of cancer cells. Altogether, our data demonstrate for the first time in an immunocompetent in vivo model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs.

<p>The file Supplementary Information contains 9 Supplementary Figures and additional Materials and Methods mainly related to experiments done during the process of the Revision. Here is a short description of each Supplementary Figure: Supplementary Figure S1. Reduction of the DC101 dosage to 10 mg/kg results in a significant, additive treatment effect in the TS/A model when combined with ATRA. Supplementary Figure S2. Growth curves showing tumor kinetics up to 9 days after stopping the treatment with DC101 and ATRA. Supplementary Figure S3. ATRA decreases the DC101-induced expression of the alternative hypoxia marker GLUT1, whereas CD8+ T-cell and NK cell populations in TS/A breast cancer tumors remain unchanged upon treatment. Supplementary Figure S4. Characterization of the proangiogenic phenotype of tumor-infiltrating MDSC. Supplementary Figure S5. Characterization of the matricellular composition in 4T1 tumors. Supplementary Figure S6. In vitro generated MDSC efficiently suppress T cell proliferation. Supplementary Figure S7. (A) Intratumoral S100A8 levels show a strong correlation with FITC-lectin leakage. (B) ATRA has no direct influence on ZO-1 protein levels in vitro. Supplementary Figure S8. The therapeutic efficiency of DC101 is not increased in S100A9 knockout bone marrow transplanted mice, which exhibit tumor-dependent S100A8 recovery. Supplementary Figure S9. Analysis of the Vegf and Fgf expression levels of mast cells and cancer associated fibroblasts in 4T1 tumors. The Supplementary Materials and Methods section contains a description of: used Reagents and proteins, quantitative PCR, sequences of oligonucleotide primers used for quantitative PCR, fluorescence activated cell sorting (FACS) of mast cells and cancer assoicated fibroblasts, bone marrow transplantation, scanning electron microscopy, western blotting, ELISA, allogeneic T cell proliferation assay, metabolomic analysis of 4T1 tumor tissue.</p>