30 research outputs found
Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3−/− mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti–PD-1 mAbs. Batf3−/− mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti–CD137- and anti–PD-1–mediated immunostimulation in tumor therapy against B16-ovalbumin–derived melanomas, whereas this function was lost in Batf3−/− mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects
A far-ultraviolet-driven photoevaporation flow observed in a protoplanetary disk
Most low-mass stars form in stellar clusters that also contain massive stars,
which are sources of far-ultraviolet (FUV) radiation. Theoretical models
predict that this FUV radiation produces photo-dissociation regions (PDRs) on
the surfaces of protoplanetary disks around low-mass stars, impacting planet
formation within the disks. We report JWST and Atacama Large Millimetere Array
observations of a FUV-irradiated protoplanetary disk in the Orion Nebula.
Emission lines are detected from the PDR; modelling their kinematics and
excitation allows us to constrain the physical conditions within the gas. We
quantify the mass-loss rate induced by the FUV irradiation, finding it is
sufficient to remove gas from the disk in less than a million years. This is
rapid enough to affect giant planet formation in the disk
PDRs4All IV. An embarrassment of riches: Aromatic infrared bands in the Orion Bar
(Abridged) Mid-infrared observations of photodissociation regions (PDRs) are
dominated by strong emission features called aromatic infrared bands (AIBs).
The most prominent AIBs are found at 3.3, 6.2, 7.7, 8.6, and 11.2 m. The
most sensitive, highest-resolution infrared spectral imaging data ever taken of
the prototypical PDR, the Orion Bar, have been captured by JWST. We provide an
inventory of the AIBs found in the Orion Bar, along with mid-IR template
spectra from five distinct regions in the Bar: the molecular PDR, the atomic
PDR, and the HII region. We use JWST NIRSpec IFU and MIRI MRS observations of
the Orion Bar from the JWST Early Release Science Program, PDRs4All (ID: 1288).
We extract five template spectra to represent the morphology and environment of
the Orion Bar PDR. The superb sensitivity and the spectral and spatial
resolution of these JWST observations reveal many details of the AIB emission
and enable an improved characterization of their detailed profile shapes and
sub-components. While the spectra are dominated by the well-known AIBs at 3.3,
6.2, 7.7, 8.6, 11.2, and 12.7 m, a wealth of weaker features and
sub-components are present. We report trends in the widths and relative
strengths of AIBs across the five template spectra. These trends yield valuable
insight into the photochemical evolution of PAHs, such as the evolution
responsible for the shift of 11.2 m AIB emission from class B in
the molecular PDR to class A in the PDR surface layers. This
photochemical evolution is driven by the increased importance of FUV processing
in the PDR surface layers, resulting in a "weeding out" of the weakest links of
the PAH family in these layers. For now, these JWST observations are consistent
with a model in which the underlying PAH family is composed of a few species:
the so-called 'grandPAHs'.Comment: 25 pages, 10 figures, to appear in A&
PDRs4All II: JWST's NIR and MIR imaging view of the Orion Nebula
The JWST has captured the most detailed and sharpest infrared images ever
taken of the inner region of the Orion Nebula, the nearest massive star
formation region, and a prototypical highly irradiated dense photo-dissociation
region (PDR). We investigate the fundamental interaction of far-ultraviolet
photons with molecular clouds. The transitions across the ionization front
(IF), dissociation front (DF), and the molecular cloud are studied at
high-angular resolution. These transitions are relevant to understanding the
effects of radiative feedback from massive stars and the dominant physical and
chemical processes that lead to the IR emission that JWST will detect in many
Galactic and extragalactic environments. Due to the proximity of the Orion
Nebula and the unprecedented angular resolution of JWST, these data reveal that
the molecular cloud borders are hyper structured at small angular scales of
0.1-1" (0.0002-0.002 pc or 40-400 au at 414 pc). A diverse set of features are
observed such as ridges, waves, globules and photoevaporated protoplanetary
disks. At the PDR atomic to molecular transition, several bright features are
detected that are associated with the highly irradiated surroundings of the
dense molecular condensations and embedded young star. Toward the Orion Bar
PDR, a highly sculpted interface is detected with sharp edges and density
increases near the IF and DF. This was predicted by previous modeling studies,
but the fronts were unresolved in most tracers. A complex, structured, and
folded DF surface was traced by the H2 lines. This dataset was used to revisit
the commonly adopted 2D PDR structure of the Orion Bar. JWST provides us with a
complete view of the PDR, all the way from the PDR edge to the substructured
dense region, and this allowed us to determine, in detail, where the emission
of the atomic and molecular lines, aromatic bands, and dust originate
PDRs4All III: JWST's NIR spectroscopic view of the Orion Bar
(Abridged) We investigate the impact of radiative feedback from massive stars
on their natal cloud and focus on the transition from the HII region to the
atomic PDR (crossing the ionisation front (IF)), and the subsequent transition
to the molecular PDR (crossing the dissociation front (DF)). We use
high-resolution near-IR integral field spectroscopic data from NIRSpec on JWST
to observe the Orion Bar PDR as part of the PDRs4All JWST Early Release Science
Program. The NIRSpec data reveal a forest of lines including, but not limited
to, HeI, HI, and CI recombination lines, ionic lines, OI and NI fluorescence
lines, Aromatic Infrared Bands (AIBs including aromatic CH, aliphatic CH, and
their CD counterparts), CO2 ice, pure rotational and ro-vibrational lines from
H2, and ro-vibrational lines HD, CO, and CH+, most of them detected for the
first time towards a PDR. Their spatial distribution resolves the H and He
ionisation structure in the Huygens region, gives insight into the geometry of
the Bar, and confirms the large-scale stratification of PDRs. We observe
numerous smaller scale structures whose typical size decreases with distance
from Ori C and IR lines from CI, if solely arising from radiative recombination
and cascade, reveal very high gas temperatures consistent with the hot
irradiated surface of small-scale dense clumps deep inside the PDR. The H2
lines reveal multiple, prominent filaments which exhibit different
characteristics. This leaves the impression of a "terraced" transition from the
predominantly atomic surface region to the CO-rich molecular zone deeper in.
This study showcases the discovery space created by JWST to further our
understanding of the impact radiation from young stars has on their natal
molecular cloud and proto-planetary disk, which touches on star- and planet
formation as well as galaxy evolution.Comment: 52 pages, 30 figures, submitted to A&
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
PDRs4All: A JWST Early Release Science Program on Radiative Feedback from Massive Stars
22 pags., 8 figs., 1 tab.Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter-and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.Support for JWST-ERS program ID 1288 was provided through grants from the STScI under NASA contract NAS5-03127 to STScI (K.G., D.V.D.P., M.R.), Univ. of Maryland (M.W., M.P.), Univ. of Michigan (E.B., F.A.), and Univ. of Toledo (T.S.-Y.L.). O.B. and E.H. are supported by the Programme National “Physique et Chimie du Milieu Interstellaire” (PCMI) of CNRS/INSU with INC/INP co-funded by CEA and CNES, and through APR grants 6315 and 6410 provided by CNES. E. P. and J.C. acknowledge support from the National Science and
Engineering Council of Canada (NSERC) Discovery Grant program (RGPIN-2020-06434 and RGPIN-2021-04197 respectively). E.P. acknowledges support from a Western Strategic Support Accelerator Grant (ROLA ID 0000050636). J.R.G. and S.C. thank the Spanish MCINN for funding support under grant PID2019-106110GB-I00. Work by M.R. and Y.O. is carried out within the Collaborative Research Centre 956, subproject C1, funded by the Deutsche Forschungsgemeinschaft (DFG)—project ID 184018867. T.O. acknowledges support from JSPS Bilateral Program, grant No. 120219939. M.P. and M.W. acknowledge support from NASA Astrophysics Data Analysis Program award #80NSSC19K0573. C.B. is grateful for an appointment at NASA Ames Research Center through the San José State University Research Foundation (NNX17AJ88A) and acknowledges support from the Internal Scientist Funding Model (ISFM) Directed Work Package at
NASA Ames titled: “Laboratory Astrophysics—The NASA Ames PAH IR Spectroscopic Database.”Peer reviewe
On the hipoxia regulation of CD137 and CD69 expression
The tumor microenvironment is characterized to be under severe conditions (nutrient shortage, low pH and oxygen deprivation) that affect not only tumor cells but also stroma and immune infiltrate. Tumor cells have developed mechanism in order to adapt their biology to such extreme circumstances. One of these adaptation strategies is the HIF-1α pathway that is activated under hypoxia (low oxygen availability) promoting angiogenesis, metabolic changes and survival.
The projects that have been carried out during this thesis are focused on the influence of hypoxia in the biology of malignant and immune cells in the tumor microenvironment regarding the regulation of two important lymphocyte receptors: CD137 and CD69.
Under hypoxic conditions tumor cells promote the alternative splicing of the co-stimulatory receptor CD137 (also known as 4-1BB) resulting in the generation of a functional soluble form of CD137 (sCD137). The secreted sCD137 binds the natural ligand of CD137 (present on APCs) preventing the CD137 ligand-mediated co-stimulation of T-lymphocytes acting as an immune-evasion mechanism. Additionally, CD137 silencing in a colon carcinoma cell line enhances the tumor growth control mediated by CD8+ T lymphocytes.
Tumor-infiltrating T lymphocytes (TILs) are also influenced by hypoxia that controls many of the mechanisms that confer T-cells a cytotoxic phenotype. TILs from transplantable and spontaneous mouse tumors express the early T-cell activation marker CD69 more intensely than lymphocytes located in a non-hypoxic tissue such as the spleen. The second study of this thesis points out that hypoxia up-regulates CD69 in T-lymphocytes undergoing TCR-CD3 activation in a HIF-1α dependent manner. Indeed, HIF-1α is able to bind a hypoxia response element (HRE) that we have found in the promoter of the human CD69 gene. In addition, in vivo staining with pimonidazole shows a correlation between hypoxia and the intensity of CD69 expression on T lymphocytes from hypoxic tissues, such as bone marrow and tumor.
These studies highlight that hypoxia plays an important role in the interplay between tumors and immune infiltrates in the tumor microenvironment
On the hipoxia regulation of CD137 and CD69 expression
The tumor microenvironment is characterized to be under severe conditions (nutrient shortage, low pH and oxygen deprivation) that affect not only tumor cells but also stroma and immune infiltrate. Tumor cells have developed mechanism in order to adapt their biology to such extreme circumstances. One of these adaptation strategies is the HIF-1α pathway that is activated under hypoxia (low oxygen availability) promoting angiogenesis, metabolic changes and survival.
The projects that have been carried out during this thesis are focused on the influence of hypoxia in the biology of malignant and immune cells in the tumor microenvironment regarding the regulation of two important lymphocyte receptors: CD137 and CD69.
Under hypoxic conditions tumor cells promote the alternative splicing of the co-stimulatory receptor CD137 (also known as 4-1BB) resulting in the generation of a functional soluble form of CD137 (sCD137). The secreted sCD137 binds the natural ligand of CD137 (present on APCs) preventing the CD137 ligand-mediated co-stimulation of T-lymphocytes acting as an immune-evasion mechanism. Additionally, CD137 silencing in a colon carcinoma cell line enhances the tumor growth control mediated by CD8+ T lymphocytes.
Tumor-infiltrating T lymphocytes (TILs) are also influenced by hypoxia that controls many of the mechanisms that confer T-cells a cytotoxic phenotype. TILs from transplantable and spontaneous mouse tumors express the early T-cell activation marker CD69 more intensely than lymphocytes located in a non-hypoxic tissue such as the spleen. The second study of this thesis points out that hypoxia up-regulates CD69 in T-lymphocytes undergoing TCR-CD3 activation in a HIF-1α dependent manner. Indeed, HIF-1α is able to bind a hypoxia response element (HRE) that we have found in the promoter of the human CD69 gene. In addition, in vivo staining with pimonidazole shows a correlation between hypoxia and the intensity of CD69 expression on T lymphocytes from hypoxic tissues, such as bone marrow and tumor.
These studies highlight that hypoxia plays an important role in the interplay between tumors and immune infiltrates in the tumor microenvironment
Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB)
TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4–1BB) stimulation to NF-κB activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD137-induced NF-κB activation in cultured cells and in gene-transferred hepatocytes in vivo, while silencing these deubiquitinases enhanced CD137 costimulation of primary human CD8 T cells. Therefore A20 and CYLD directly downregulate the signaling from a T and NK-cell costimulatory receptor under exploitation for cancer immunotherapy in clinical trials.MICINN (SAF2011-22831 and SAF2014-52361-R) (I.M), Departamento de Salud del Gobierno de Navarra, Redes temáticas de investigación cooperativa RETICC, European Commission VII Framework and Horizon 2020 programs (AICR and PROCROP), Fundación de la Asociación Española Contra el Cáncer (AECC), Fundación BBVA. MER-R receives support for a Rio Ortega Contract.Peer reviewe