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The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14 + DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system. Conventional co-culture systems often lack physiological complexity of the tumor microenvironment. Here, the authors report an organotypic skin melanoma culture and use this model to investigate the tumor induced suppression on dendritic cells.

Background: Host immunity is emerging as a key player in the prognosis and response to treatment of cancer patients. However, the impact of the immune system and its modulation by therapies are unknown in rare soft tissue sarcomas such as solitary fibrous tumours (SFTs), whose management in the advanced forms includes anti-angiogenic therapy. Here, we studied the in situ and systemic immune status of advanced SFT patients and the effects of sunitinib malate (SM) in association with the clinical efficacy. Methods: Immune contexture of SFTs was assessed by immunohistochemistry in lesions from untreated or SM-treated patients. Frequency of circulating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and T-cell functions was assessed ex vivo in SFT patients prior and during anti-angiogenic therapy. Patients with long-term tumour control were included to correlate immune profiles and clinical responses. Results: Anti-angiogenic naïve SFT lesions were heavily infiltrated by CD163 + CD14 + CD68 − and CD163 + CD14 − CD68 − myeloid cells but devoid of T cells. Conversely, post-SM tumours acquired a new subset of CD68 + CD14 + myeloid cells and displayed traits of an on-going adaptive immunity, strongly enriched in activated CD8 + and CD4 + T cells. These changes at the tumour site paralleled the alleviation of systemic immunosuppression and the drop in the frequency of circulating monocytic MDSCs (mMDSCs) and granulocytic MDSCs (gMDSCs). Rebound in the number of mMDSCs, but not of gMDSCs occurred at disease progression, and a reduced percentages of mMDSCs, comparable to those found in healthy donors (HDs), endured only in the SM-responsive patients. Conclusions: The immune contexture of SFT patients is heavily involved in anti-angiogenic therapy and it could be exploited to achieve more durable disease control through immune-based combination strategies.

Background Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a central role in the immune system, orchestrating immune response against tumors. We previously demonstrated that DC-based vaccination effectively induces anti-tumor immunity, yet at the same time showing a robust safety profile, making this treatment a potential candidate for effective adjuvant immunotherapy. To explore this possibility, we designed a randomized phase II trial (EudraCT no. 2014-005123-27) to provide a complementary autologous DC vaccination to patients (pts) with resected stage III/IV melanoma. Methods Overall, a total of 18 eligible pts were included in this study, 10 of whom received 6 monthly DC vaccination cycles combined with IL-2 administration (arm A), and 8 pts were enrolled in the follow-up observational cohort (arm B). A deep immune biomarkers profiling by multiplex immunoassay, human leukocyte antigens (HLA) typing, multiparametric flow cytometry and in situ tumor microenvironment analysis was performed for the entire pts cohort. The immunological response was assessed in vivo by DTH test and ex vivo against selected melanoma-associated antigens applying the IFN-γ ELISPOT assay. Results Pts receiving DC vaccination showed a better relapse-free survival compared to the observational cohort (median 6.6 months, 95% CI, 2.3–not reached (nr) (arm A) vs 5.2 months, 95% CI, 2.5–nr (arm B), not significant), with a favorable trends for female pts (median 15.5 months, 95% CI, 2.6–nr (female) vs 3.3, 95% CI, 2.3–nr (male)), pts with less than 60 years (median 22.5 months, 95% CI, 2.6–nr (age < 60) vs 4.7 months, 95% CI, 2.3–nr (age ≥ 60), and pts with wild-type BRAF status (median 22.5 months, 95% CI, 8.6–nr (BRAF wt) vs 3.8 months, 95% CI, 2.3–nr (BRAF mutated). The toxicity profile was favourable, with no severe adverse events and only mild, manageable reactions. Moreover, additional immune response data suggested increased immune modulation in vaccinated patients, which may reflect a shift in immune dynamics. Conclusions Our findings support the safety and tolerability of DC vaccination as an adjuvant treatment for melanoma, demonstrating significant immune modulation at both the tumor site and peripherally in relapsed and non-relapsed patients. These results highlight the potential of autologous, personalised DC-based therapies and pave the way for the development of innovative immunotherapy combinations in future treatment strategies. Trial registration ClinicalTrials.gov NCT02718391; EudraCT no. 2014-005123-27.

The frequency and function of regulatory T cells (Tregs) were studied in stage II–III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low-dose interleukin-2 (IL-2). Tregs were analyzed in the lymph nodes (LNs) of stage III patients who were undergoing complete lymph node dissection and in peripheral blood mononuclear cells (PBMCs) collected before vaccination and at different time points during the vaccination period. The LNs of the vaccinated patients, which were surgically removed after two rounds of vaccination and one dose of CTX, displayed a low frequency of Tregs and a less immunosuppressive environment compared with those of the untreated patients. The accurate time-course analysis of the PBMCs of patients enrolled in the vaccination arm indicated a limited and transient modulation in the frequencies of Tregs in PBMCs collected after low-dose CTX administration and a strong Treg boost in those PBMCs collected after low-dose IL-2 administration. However, a fraction of the IL-2-boosted Tregs was functionally modulated to a Th-1-like phenotype in the vaccinated patients. Moreover, low-dose IL-2 promoted the concomitant expansion of conventional activated CD4 + T cells. Despite the amplification of Tregs, IL-2 administration maintained or further increased the number of antigen-specific CD8 + T cells that were induced by vaccination as demonstrated by the ex vivo human leukocyte antigen-multimer staining and IFN-γ ELISpot assays. Our study suggests that the use of CTX as a Treg modulator should be revised in terms of the administration schedule and of patients who may benefit from this drug treatment. Despite the Treg expansion that was observed in this study, low-dose IL-2 is not detrimental to the functional activities of vaccine-primed CD8 + T cell effectors when used in the inflammatory environment of vaccination.

Survivin is an intracellular tumor-associated antigen that is broadly expressed in a large variety of tumors and also in tumor associated endothelial cells but mostly absent in differentiated tissues. Naked DNA vaccines targeting survivin have been shown to induce T cell as well as humoral immune responses in mice. However, the lack of epitope-specific CD8+ T cell detection and modest tumor protection observed highlight the need for further improvements to develop effective survivin DNA vaccination approaches. Here, the efficacy of a human survivin DNA vaccine delivered by intradermal electroporation (EP) was tested. The CD8+ T cell epitope surv₂₀₋₂₈ restricted to H-2 Db was identified based on in-silico epitope prediction algorithms and binding to MHC class I molecules. Intradermal DNA EP of mice with a human survivin encoding plasmid generated CD8+ cytotoxic T lymphocyte (CTL) responses cross-reactive with the mouse epitope surv₂₀₋₂₈, as determined by intracellular IFN-γ staining, suggesting that self-tolerance has been broken. Survivin-specific CTLs displayed an activated effector phenotype as determined by CD44 and CD107 up-regulation. Vaccinated mice displayed specific cytotoxic activity against B16 and peptide-pulsed RMA-S cells in vitro as well as against surv₂₀₋₂₈ peptide-pulsed target cells in vivo. Importantly, intradermal EP with a survivin DNA vaccine suppressed angiogenesis in vivo and elicited protection against highly aggressive syngeneic B16 melanoma tumor challenge. We conclude that intradermal EP is an attractive method for delivering a survivin DNA vaccine that should be explored also in clinical studies.

(Abridged) Exoplanetary research has provided us with exciting discoveries of planets around very low-mass (VLM) stars (e.g., TRAPPIST-1 and Proxima Centauri). However, current theoretical models strive to explain planet formation in these conditions and do not predict the development of giant planets. Recent high-resolution observations from ALMA of the disk around CIDA 1, a VLM star in Taurus, show substructures hinting at the presence of a massive planet. We aim to reproduce the dust ring of CIDA 1, observed in the dust continuum emission in ALMA Band 7 (0.9 mm) and Band 4 (2.1 mm), along with its \\(^{12}\\)CO (J=3-2) and \\(^{13}\\)CO (J=3-2) channel maps, assuming the structures are shaped by the interaction of the disk with a massive planet. We seek to retrieve the mass and position of the putative planet. We model the protoplanetary disk with a set of hydrodynamical simulations, varying the mass and locations of the embedded planet. We compute the dust and gas emission using radiative transfer simulations, and, finally, we obtain the synthetic observations treating the images as the actual ALMA observations. Our models indicate that a planet with a minimum mass of \\(\\sim1.4\\,\\text{M}_\\text{Jup}\\) orbiting at a distance of \\(\\sim 9-10\\) au can explain the morphology and location of the observed dust ring at Band 7 and Band 4. We can reproduce the low spectral index (\\(\\sim 2\\)) observed where the dust ring is detected. Our synthetic images reproduce the morphology of the \\(^{12}\\)CO and \\(^{13}\\)CO observed channel maps where the cloud absorption allowed a detection. Applying an empirical relation between planet mass and gap width in the dust, we predict a maximum planet mass of \\(\\sim4 - 8\\,\\text{M}_\\text{Jup}\\). Our results suggest the presence of a massive planet orbiting CIDA 1, thus challenging our understanding of planet formation around VLM stars.

Observations of protoplanetary disks around very low-mass stars and brown dwarfs remain challenging and little is known about their properties. The disk around CIDA1 (\\(\\sim\\)0.1-0.2\\(M_\\odot\\)) is one of the very few known disks that host a large cavity (20au radius in size) around a very low-mass star. We present new ALMA observations at Band7 (0.9mm) and Band4 (2.1mm) of CIDA1 with a resolution of \\(\\sim 0.05''\\times 0.034''\\). These new ALMA observations reveal a very bright and unresolved inner disk, a shallow spectral index of the dust emission (\\(\\sim2\\)), and a complex morphology of a ring located at 20au. We also present X-Shooter (VLT) observations that confirm the high accretion rate of CIDA1 of \\(\\dot{M}_{\\rm acc}\\)=1.4 \\(\\times~10^{-8}M_\\odot\\)/yr. This high value of \\(\\dot{M}_{\\rm acc}\\), the observed inner disk, and the large cavity of 20au exclude models of photo-evaporation to explain the observed cavity. When comparing these observations with models that combine planet-disk interaction, dust evolution, and radiative transfer, we exclude planets more massive than 0.5\\(M_{\\rm{Jup}}\\) as the potential origin of the large cavity because with these it is difficult to maintain a long-lived and bright inner disk. Even in this planet mass regime, an additional physical process may be needed to stop the particles from migrating inwards and to maintain a bright inner disk on timescales of millions of years. Such mechanisms include a trap formed by a very close-in extra planet or the inner edge of a dead zone. The low spectral index of the disk around CIDA1 is difficult to explain and challenges our current dust evolution models, in particular processes like fragmentation, growth, and diffusion of particles inside pressure bumps.

In this paper we analyze new observations from ALMA and VLA, at a high angular resolution corresponding to 5 - 8 au, of the protoplanetary disk around HD 163296 to determine the dust spatial distribution and grain properties. We fit the spectral energy distribution as a function of the radius at five wavelengths from 0.9 to 9\\,mm, using a simple power law and a physical model based on an analytic description of radiative transfer that includes isothermal scattering. We considered eight dust populations and compared the models' performance using Bayesian evidence. Our analysis shows that the moderately high optical depth (\\(\\tau\\)>1) at \\(\\lambda \\leq\\) 1.3 mm in the dust rings artificially lower the millimeter spectral index, which should therefore not be considered as a reliable direct proxy of the dust properties and especially the grain size. We find that the outer disk is composed of small grains on the order of 200 \\(\\mu\\)m with no significant difference between rings at 66 and 100 au and the adjacent gaps, while in the innermost 30 au, larger grains (\\(\\geq\\)mm) could be present. We show that the assumptions on the dust composition have a strong impact on the derived surface densities and grain size. In particular, increasing the porosity of the grains to 80\\% results in a total dust mass about five times higher with respect to grains with 25\\% porosity. Finally, we find that the derived opacities as a function of frequency deviate from a simple power law and that grains with a lower porosity seem to better reproduce the observations of HD163296. While we do not find evidence of differential trapping in the rings of HD163296, our overall results are consistent with the postulated presence of giant planets affecting the dust temperature structure and surface density, and possibly originating a second-generation dust population of small grains.

The formation of multiple stellar systems is a natural by-product of the star-formation process, and its impact on the properties of protoplanetary discs and on the formation of planets is still to be fully understood. To date, no detailed uniform study of the gas emission from a sample of protoplanetary discs around multiple stellar systems has been performed. Here we analyse new ALMA observations at a \\(\\sim\\)21 au resolution of the molecular CO gas emission targeting discs in eight multiple stellar systems in the Taurus star-forming regions. \\(^{12}\\)CO gas emission is detected around all primaries and in seven companions. With these data, we estimate the inclination and the position angle for all primary discs and for five secondary or tertiary discs, and measure the gas disc radii of these objects with a cumulative flux technique on the spatially resolved zeroth moment images. When considering the radius including 95\\% of the flux as a metric, the estimated gas disc size in multiple stellar systems is found to be on average \\(\\sim 4.2\\) times larger than the dust disc size. This ratio is higher than what was recently found in a population of more isolated and single systems. On the contrary, when considering the radius including 68\\% of the flux, no difference between multiple and single discs is found in the distribution of ratios. This discrepancy is due to the sharp truncation of the outer dusty disc observed in multiple stellar systems. The measured gas disc sizes are consistent with tidal truncation models in multiple stellar systems assuming eccentricities of \\(\\sim0.15\\)-\\(0.5\\), as expected in typical binary systems.

To determine the origin of the spiral structure observed in the dust continuum emission of Elias 2-27 we analyze multi-wavelength continuum ALMA data with a resolution of \\(\\)0.2 arcsec (\\(\\)23au) at 0.89, 1.3 and 3.3mm. We also study the kinematics of the disk with \\(^13\\)CO and C\\(^18\\)O ALMA observations in the \\(J=\\)3-2 transition. The spiral arm morphology is recovered at all wavelengths in the dust continuum observations, where we measure contrast and spectral index variations along the spiral arms and detect subtle dust-trapping signatures. We determine that the emission from the midplane is cold and interpret the optical depth results as signatures of a higher disk mass than previous constraints. From the gas data, we search for deviations from Keplerian motion and trace the morphology of the emitting surfaces and the velocity profiles. We find an azimuthally varying emission layer height in the system, large-scale emission surrounding the disk, and strong perturbations in the channel maps, co-located with the spirals. Additionally, we develop multigrain dust and gas SPH simulations of a gravitationally unstable disk and compare them to the observations. Given the large scale emission and highly perturbed gas structure, together with the comparison of continuum observations to theoretical predictions, we propose infall-triggered gravitational instabilities as origin for the observed spiral structure.