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Abstract Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer T (^AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into^AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced^AlloCAR-NKT cells with high yield and purity. We generated^AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of^AlloCAR-NKT cells support their potential for clinical translation. 

Abstract Indian Ocean meridional heat transport (MHT_IO) drives climate and ecosystem impacts, through changes to ocean temperature. Improved understanding of natural variability in tropical and subtropical MHT_IOis needed to contextualize observations and future projections. Previous studies suggest that El Niño‐Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) can drive variability in MHT_IO. However, it is unclear whether internally generated IOD can drive variability in MHT_IO, or if the apparent relationship between IOD and MHT_IOarises because both are modulated by ENSO. Here, we use a model experiment which dynamically removes ENSO to determine the role of internally forced IOD on MHT_IO. We find that IOD is not linked to anomalies in MHT_IO. Nevertheless, internal atmospheric variability drives significant MHT_IOvariability. There is little evidence for decadal or multidecadal variability in MHT_IO, suggesting this may be a region where an anthropogenic trend rises above the level of internal variability sooner. 

Abstract Investigating Pacific Meridional Modes (PMM) without the influence of tropical Pacific variability is technically difficult if based on observations or fully coupled model simulations due to their overlapping spatial structures. To confront this issue, the present study investigates both North (NPMM) and South PMM (SPMM) in terms of their associated atmospheric forcing and response processes based on a mechanically decoupled climate model simulation. In this experiment, the climatological wind stress is prescribed over the tropical Pacific, which effectively removes dynamically coupled tropical Pacific variability (e.g., the El Niño-Southern Oscillation). Interannual NPMM in this experiment is forced not only by the North Pacific Oscillation, but also by a North Pacific tripole (NPT) pattern of atmospheric internal variability, which primarily forces decadal NPMM variability. Interannual and decadal variability of the SPMM is partly forced by the South Pacific Oscillation. In turn, both interannual and decadal NPMM variability can excite atmospheric teleconnections over the Northern Hemisphere extratropics by influencing the meridional displacement of the climatological intertropical convergence zone throughout the whole year. Similarly, both interannual and decadal SPMM variability can also excite atmospheric teleconnections over the Southern Hemisphere extratropics by extending/shrinking the climatological South Pacific convergence zone in all seasons. Our results highlight a new poleward pathway by which both the NPMM and SPMM feed back to the extratropical climate, in addition to the equatorward influence on tropical Pacific variability. 

Abstract Identifying the origins of wintertime climate variations in the Northern Hemisphere requires careful attribution of the role of El Niño–Southern Oscillation (ENSO). For example, Aleutian low variability arises from internal atmospheric dynamics and is remotely forced mainly via ENSO. How ENSO modifies the local sea surface temperature (SST) and North American precipitation responses to Aleutian low variability remains unclear, as teasing out the ENSO signal is difficult. This study utilizes carefully designed coupled model experiments to address this issue. In the absence of ENSO, a deeper Aleutian low drives a positive Pacific decadal oscillation (PDO)-like SST response. However, unlike the observed PDO pattern, a coherent zonal band of turbulent heat flux–driven warm SST anomalies develops throughout the subtropical North Pacific. Furthermore, non-ENSO Aleutian low variability is associated with a large-scale atmospheric circulation pattern confined over the North Pacific and North America and dry precipitation anomalies across the southeastern United States. When ENSO is included in the forcing of Aleutian low variability in the experiments, the ENSO teleconnection modulates the turbulent heat fluxes and damps the subtropical SST anomalies induced by non-ENSO Aleutian low variability. Inclusion of ENSO forcing results in wet precipitation anomalies across the southeastern United States, unlike when the Aleutian low is driven by non-ENSO sources. Hence, we find that the ENSO teleconnection acts to destructively interfere with the subtropical North Pacific SST and southeastern United States precipitation signals associated with non-ENSO Aleutian low variability. 

Variations in the Atlantic meridional overturning circulation (AMOC) driven by buoyancy forcing are typically characterized as having a low-frequency time scale, interhemispheric structure, cross-equatorial heat transport, and linkages to the strength of Northern Hemisphere gyre circulations and the Gulf Stream. This study first tests whether these attributes ascribed to the AMOC are reproduced in a coupled model that is mechanically decoupled and, hence, is only buoyancy coupled. Overall, the mechanically decoupled model reproduces these attributes, with the exception that in the subpolar gyre, buoyancy drives AMOC variations on interannual to multidecadal time scales, yet only the multidecadal variations penetrate into the subtropics. A stronger AMOC is associated with a strengthening of the Northern Hemisphere gyre circulations, Gulf Stream, and northward oceanic heat transport throughout the basin. We then determine whether the characteristics in the mechanically decoupled model can be recovered by low-pass filtering the AMOC in a fully coupled version of the same model, a common approach used to isolate the buoyancy-driven AMOC. A major conclusion is that low-pass filtering the AMOC in the fully coupled model reproduces the buoyancy-driven AMOC pattern and most of the associated attributes, but not the statistics of the temporal variability. The strength of the AMOC–Gulf Stream connection is also not reproduced. The analyses reveal caveats that must be considered when choosing indexes and filtering techniques to estimate the buoyancy-driven AMOC. Results also provide insight on the latitudinal dependence of time scales and drivers of ocean circulation variability in coupled models, with potential implications for measurement and detection of the buoyancy-driven AMOC in the real world.