0000000001320884
AUTHOR
Fang Zhao
showing 10 related works from this author
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
2016
Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to …
Differential influence of vemurafenib and dabrafenib on patient lymphocytes despite similar clinical efficacy in melanoma
2014
Background: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts’ immune system. Patients and methods: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. Results: Progression-free survival (PFS) as well as overall survival (O…
Climate Extreme Versus Carbon Extreme: Responses of Terrestrial Carbon Fluxes to Temperature and Precipitation
2020
International audience; Carbon fluxes at the land-atmosphere interface are strongly influenced by weather and climate conditions. Yet what is usually known as “climate extremes” does not always translate into very high or low carbon fluxes or so-called “carbon extremes.” To reveal the patterns of how climate extremes influence terrestrial carbon fluxes, we analyzed the interannual variations in ecosystem carbon fluxes simulated by the Terrestrial Biosphere Models (TBMs) in the Inter-Sectoral Impact Model Intercomparison Project. At the global level, TBMs simulated reduced ecosystem net primary productivity (NPP; 18.5 ± 9.3 g C m−2 yr−1), but enhanced heterotrophic respiration (Rh; 7 ± 4.6 g…
Evolution of melanoma cross-resistance to CD8⁺ T cells and MAPK inhibition in the course of BRAFi treatment
2018
The profound but frequently transient clinical responses to BRAFV600 inhibitor (BRAFi) treatment in melanoma emphasize the need for combinatorial therapies. Multiple clinical trials combining BRAFi and immunotherapy are under way to further enhance therapeutic responses. However, to which extent BRAFV600 inhibition may affect melanoma immunogenicity over time remains largely unknown. To support the development of an optimal treatment protocol, we studied the impact of prolonged BRAFi exposure on the recognition of melanoma cells by T cells in different patient models. We demonstrate that autologous CD8+ tumor-infiltrating lymphocytes (TILs) efficiently recognized short-term (3, 7 days) BRAF…
Genetic evolution of T-cell resistance in the course of melanoma progression
2014
Abstract Purpose: CD8+ T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells. Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell–stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alteratio…
Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency
2016
Abstract Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA …
7 Evolution of cross-resistance to CD8+ T cells in the course of BRAF and MEK inhibitor treatment in BRAFV600E melanoma
2018
Introduction The BRAFV600 mutation, expressed in approximately 50% of melanomas, mediates constitutive activation of the BRAF-MEK-ERK in the MAPK signalling pathway and therefore tumour proliferation. Rapid and high rate of clinical responses can be achieved by targeting this axis using BRAF V600 inhibitor (BRAFi) as single therapy or the combination of BRAFi and MEKi (BRAFi/MEKi). But still disease progresses in the majority of treated patients due to acquired resistance in tumour cells. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. However, to which extent BRAFi may affect melanoma immunogenicity over time remains largely unknown.…
Projecting Exposure to Extreme Climate Impact Events Across Six Event Categories and Three Spatial Scales
2020
Summarization: The extent and impact of climate‐related extreme events depend on the underlying meteorological, hydrological, or climatological drivers as well as on human factors such as land use or population density. Here we quantify the pure effect of historical and future climate change on the exposure of land and population to extreme climate impact events using an unprecedentedly large ensemble of harmonized climate impact simulations from the Inter‐Sectoral Impact Model Intercomparison Project phase 2b. Our results indicate that global warming has already more than doubled both the global land area and the global population annually exposed to all six categories of extreme events co…
A design for an electromagnetic filter for precision energy measurements at the tritium endpoint
2019
We present a detailed description of the electromagnetic filter for the PTOLEMY project to directly detect the Cosmic Neutrino Background (CNB). Starting with an initial estimate for the orbital magnetic moment, the higher-order drift process of E×B is configured to balance the gradient-B drift motion of the electron in such a way as to guide the trajectory into the standing voltage potential along the mid-plane of the filter. As a function of drift distance along the length of the filter, the filter zooms in with exponentially increasing precision on the transverse velocity component of the electron kinetic energy. This yields a linear dimension for the total filter length that is exceptio…
Land area fractions and population fractions exposed to extreme climate impact events derived from ISIMIP2b output data
2020
This dataset contains the land area fractions and population fractions exposed ('le' for land exposed and 'pe' for population exposed) to the following six extreme climate impact events: crop failures (lec/pec), drought (led/ped), heatwaves (leh/peh), river floods (ler/per), tropical cyclones (let/pet) and wildfire (lew/pew). It is the data behind Lange et al., 2020. The data are provided on a global 0.5° grid and in annual time steps. It was derived from multi-model climate impacts simulations generated within the second round (ISIMIP2b, https://www.isimip.org/protocol/2b, Frieler et al., 2017) of the Intersectoral Impact Model Intercomparison Project (ISIMIP, https://www.isimip.org). The …