Role of Activin-A signaling in melanoma

Cutaneous melanomas arise from transformed skin melanocytes. While accounting for only 1% of skin malignancies, melanoma is responsible for the majority of skin cancer-related deaths. Owing to lifestyle changes and increased exposure to sunlight, melanoma occurrence is on the rise in developed countries. Identification of the molecular mechanisms driving melanoma formation led to the development of new classes of therapeutics which revolutionized the standard of care. Among these, small molecule inhibitors targeting the MAPK pathway and immune checkpoint inhibitors resulted in unprecedented clinical success. Nevertheless, many patients still do not benefit from these therapies. Activin-A, a secreted ligand of the TGF-β superfamily, was recently found to be overexpressed in melanoma. However, whether Activin-A signaling promotes melanoma progression or therapy resistance is unknown. In this thesis, the contributions of autocrine and paracrine Activin-A signaling to melanoma growth are analyzed using lentiviral expression in melanoma cells of a constitutively active mutant type I Activin receptor (caALK4), of secreted Activin-A (gain-of-function), or of a ligand trap (loss-of-function). Paradoxically, while forced ALK4 signaling in melanoma grafts restored tumor suppression by inhibiting tumor cell survival and proliferation, transgenic Activin-A accelerated tumor growth. Conversely, expression of a ligand trap comprising the extracellular domain of Activin receptor IIB fused to human Fc (AIIB-Fc) slowed melanoma growth. Importantly, in immunodeficient Rag1-/- mice, effects of paracrine Activin-A gain and loss-of-function were abrogated, suggesting that Activin-A promotes melanoma progression by inhibiting the adaptive anti-tumor response. Flow cytometry analysis of tumor immune infiltrates combined with antibody-mediated cell depletion experiments confirmed that Activin-A promotes melanoma progression by inhibiting CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, inhibition of endogenous Activin-A sensitized a treatment-resistant melanoma model to immune checkpoint inhibition by anti-PD1 and anti-CTLA4 antibodies. Activin-A therefore emerges as a promising target to improve immunotherapy outcome in melanoma

Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma

Background Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear. Methods We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF -driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models. Results We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8 + T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/ INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models. Conclusions Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.info:eu-repo/semantics/publishe

Performance of the ALICE Electromagnetic Calorimeter

International audienceThe performance of the electromagnetic calorimeter of theALICE experiment during operation in 2010–2018 at the Large HadronCollider is presented. After a short introduction into the design,readout, and trigger capabilities of the detector, the proceduresfor data taking, reconstruction, and validation are explained. Themethods used for the calibration and various derived corrections arepresented in detail. Subsequently, the capabilities of thecalorimeter to reconstruct and measure photons, light mesons,electrons and jets are discussed. The performance of thecalorimeter is illustrated mainly with data obtained with test beamsat the Proton Synchrotron and Super Proton Synchrotron or inproton-proton collisions at √s = 13 TeV, and compared tosimulations

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used