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AbstractNatural killer (NK) cell function within tissues extends beyond exerting cytotoxicity, encompassing a range of functions that are just starting to become fully elucidated. In the context of human placentation, NK cells play a key role in enabling initial placentation, which is associated with the acquisition of tolerance-like properties. If and to which extent NK cells maintain these tolerance-like properties over the course of human pregnancy is still poorly understood. We asked if NK cells isolated from the decidual-placental interface of full-term human pregnancies are able to exert effector function. We observed a significant and striking lack in the ability of NK cells isolated from the decidual-placental interface (DPI) to produce interferon-g (IFN-γ) in response to the activating cytokines interleukin (IL)-12, IL-15, and IL-18. In contrast, NK cells from the decidua retained their responsiveness to cytokine-mediated activation. Notably, CD103+CD69+ tissue-resident NK cells were present in both DPI and decidua, yet exhibited distinct effector function from one another. Using high-parameter flow cytometry and single-cell sequencing, we found that this functional discrepancy was not directly predictable based on their cell surface phenotype or cell transcript. Together, our findings reveal the presence of distinct functional resident NK cell populations in 2 anatomically adjacent tissues at healthy full-term pregnancies.

Neoadjuvant chemoimmunotherapy offers promise to improve outcomes for patients with resectable non-small cell lung cancer (NSCLC). Yet not all patients derive treatment benefits, and reliable biomarkers of response are still lacking. We here assess the long-term clinical outcome of neoadjuvant chemotherapy and perioperative anti-PD-L1 inhibition in resectable stage IIIA NSCLC in the SAKK 16/14 trial and provide a comprehensive characterization of anti-tumor immune responses for biomarker-based treatment personalization. We report secondary outcomes of median event-free survival (EFS) of 4.0 years and median overall survival not being reached after a median follow-up of 5.4 years. Computer-aided spatial image analysis emphasizes the importance of CD8+ T cell positioning in tumors, and larger tertiary lymphoid structures in pre-treatment biopsies correlate with improved EFS. Genomic techniques reveal the association of intratumoral TCR diversity with response. Finally, circulating proliferating CD39+ PD-1+ CD8+ T cells and elevated levels of CCL15 post-treatment are seen in patients with sustained therapeutic benefit. NCT02572843. Neoadjuvant immunochemotherapy against NSCLC has been tested in clinical trials. Here, the authors follow up longer-term survival and measure immune cell phenotype changes in a single-arm phase II clinical trial of neoadjuvant immunochemotherapy, indicating association of intratumoural TCR diversity and CD8 T cell positioning.

Aging negatively impacts proteasome activity and/or content, and this impairment contributes to disrupted protein homeostasis and cellular dysfunction. However, little is known about proteasome complex dynamics during aging, particularly in the context of immunosenescence. Indeed, only limited data are available on the immunoproteasome, a specialized variant expressed in immune cells. We establish an in vitro model of monocyte-derived human macrophages that develop a senescence-like phenotype upon long-term culture. Our data demonstrate that immunoproteasome complexes undergo deep structural and functional alterations, with the downregulation of immunosubunit expression at the mRNA and protein level, uncapping of the 20S catalytic particle by the PA28αβ regulator, and loss of activity. Immunosubunits are partly replaced by their constitutive counterparts with a shift toward the building of 19S-capped 20S complexes to maintain proteostasis. Similar proteasome dynamics are found in the lymph nodes of aged C57BL/6 and BTBR mice, the latter of which have a naturally activated immune system. Overall, these findings propose long-term cultures of human monocyte-derived macrophages as a model to study macrophage senescence. They also provide a molecular rationale for immunoproteasome dysfunction with remodeling of the proteasome, indicating that the loss of the PA28αβ regulator is a critical event and a hallmark of immunosenescence. A study on proteasome complex dynamics in an in vitro model of senescent human macrophages and in the lymph nodes of aged mice reveals immunoproteasome remodeling and the loss of PA28αβ regulator capping as hallmarks of immunosenescence.