Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1–3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.

Amorphous metallic alloys are among the most recent class of metallic materials. [1][2][3] Indeed, low glass forming ability (GFA) of major alloys induces manufacturing into thin ribbons shape (thickness < 100 mm) since the 1960s. The development of bulk parts with reasonable dimensions is more recent (early 1990s), and it still concerns small variety of alloys having high GFA. The formation of metallic glasses (MGs) is kinetically controlled and obeys empirical rules first stated by Inoue. [4] Many metals can be processed in MG form, such as Zr, Ti, Ni, or Fe, resulting in reasonable coverage domains of properties (mechanical, magnetic, resistance to corrosion, wear). [5][6][7] Amorphous alloys present neither long-range ordering nor structural defects and then do not experience homogenous distribution of defects for strain accommodation, like in crystalline alloys. In contrast, it follows that MG possess high strength close to the theoretical s max % E/20, no macroscopic ductility and high resilience owing to a moderate Young's modulus (similar to those of their crystalline counterparts) and an average 2% elastic deformation.Bulk MGs are essentially manufactured using casting and rapid quenching techniques, thus limiting shapes and dimensions of the available parts. [8] One promising way consists in manufacturing bulk parts from fine amorphous powders, even having a low GFA. [9] Atomization of MG powders have been studied since the early 1980s, [10] and attempts for sintering were carried out by extrusion, [11] hot pressing, [12] and more recently spark plasma sintering (SPS). [13][14][15][16][17][18][19] This paper reports on an analysis of SPS consolidation of a Zr 57 Cu 20 Al 10 Ni 8 Ti 5 MG produced by high-pressure gas atomization. This MG was extensively studied in its bulk form for its structure, thermal, and mechanical behavior and is then the relevant reference for comparison with sintered parts. [20,21] Systematic thermal and structural analyses of SPS consolidated powders with various grain sizes have been performed to identify specific SPS densification and consolidation mechanisms. Moreover, local transmission electron microscopy (TEM) analyses of the specimens point out occurrence, with clear evidences, of some physical events not observable in crystalline solids, as for example temperature overshoot revealed by partial devitrification. This study aims to approach the specific mechanisms of sintering through SPS of MGs, with particular interest in phenomena localized at the particle contacts (necks).

TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.

IntroductionIn rainfed agricultural systems, sustainable and efficient water management practices are key to improved agricultural productivity and natural resource management. The agricultural system in sub-Saharan Africa (SSA) relies heavily on the availability of rainfall. With the erratic and unreliable rainfall pattern associated with poor and fragile soils, agricultural productivity has remained very low over the years. Much of the SSA agricultural land has been degraded with low fertility as a result of ongoing cultivation and wind and water erosion. This has resulted in an increased food shortage due to the ever-increasing population and land degradation. Better agricultural and nutritional security are further hampered by the lack of reliable access to the available water resources in the subsurface hydrological system.MethodsThis study used socio-economic data from 112 farm households and Boolean and Fuzzy methods to understand farmers' perceptions and identify suitable areas to implement Solar Based Irrigation Systems (SBISs) in the agro-ecologies of Bougouni and Koutiala districts of southern Mali.Results and discussionResults revealed that the usage of SBISs has been recent (4.5 years), majorly (77%) constructed by donor-funded projects mainly for domestic water use and livestock (88%). With regards to irrigation, vegetable production was the dominant water use (60%) enabling rural farm households to gain over 40% of extra household income during the dry season. Results further showed that 4,274 km2 (22%) of the total land area for the Bougouni district, and 1,722 km2 (18%) of the Koutiala district are suitable for solar-based irrigation. The affordability of solar panels in many places makes SBISs to be an emerging climate-smart technology for most rural Malian populations.